JP2007500707A - Biarylheterocyclic amines, amides and sulfur-containing compounds and methods for making and using the compounds - Google Patents

Abstract

The present invention relates generally to the fields of anti-infectives, anti-proliferative agents, anti-inflammatory agents and prokinetic agents. More specifically, the present invention relates to a family of biaryl heterocyclic amine, amide and sulfur-containing compounds useful as those agents.

Description

Detailed Description of the Invention

(Related application)
This application claims the benefit and priority of US Patent Application No. 60 / 490,855, filed July 29, 2003, which forms part of this specification.

(Technical field)
The present invention generally relates to the fields of anti-infectives, anti-proliferative agents, anti-inflammatory agents, and prokinetic agents. More specifically, the present invention relates to a family of biaryl heterocyclic amine and amide compounds useful as therapeutic agents.

(Background technology)
Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, a number of compounds have been discovered or specifically designed for use as antibiotics. In the past, it was believed that infectious diseases could be completely controlled or eradicated with the use of their therapeutic agents. However, these beliefs are swayed by the fact that cells or microbial strains that are resistant to currently effective therapeutic agents continue to evolve. In fact, virtually every antibacterial agent being developed for clinical use finally encounters the problem of emergence of resistant bacteria. For example, gram-positive bacteria such as methicillin-resistant staphylocci, penicillin-resistant streptococci, and vancomycin-resistant enterococci have occurred, which can cause serious consequences and lethality in patients infected with those resistant bacteria. Even results can be caused. Bacteria have emerged that are resistant to macrolide antibiotics (antibiotics based on 14-16 membered lactone rings). Also, for example, H. H. influenzae, and M. pneumoniae. Gram-negative bacteria such as catarrhalis have been identified. For example, by FD Lowry, “Antimicrobial Resistance: The Example of Staphylococcus aureus”, J. Clin. Invest., 2003, 111 (9), 1265-1273; and by Gold, HS and Mollering, RC, Jr. See Antimicrobial-Drug Resistance, N. Engl. J. Med., 1996, 335, 1445-53.

  The problem of resistance is not limited to the field of anti-infectives because resistance is also encountered with anti-proliferative agents used in cancer chemotherapy. Accordingly, there is a need for new anti-infective and anti-proliferative agents that are effective against both resistant bacteria and resistant strains of cancer cells.

In the field of antibiotics, N-[(5S) -3- [3-fluoro-4- (4-morpholinyl), an antibiotic containing an oxazolidinone ring, despite the problem of increased antibiotic resistance ) Phenyl] -2-oxo-5-oxazolidinyl] methylacetamide (known as linezolid and sold under the trade name Zyvox® ⁽ see Compound A)) For approval in the United States in 2000, a new major class of antibiotics has been developed for clinical use. See RC Moellering, Jr., "Linezolid: The First Oxazolidinone Antimicrobial", Annals of Internal Medicine, 2003, 138 (2), 135-142.

  Linezolid is approved for use as an antibacterial agent that is active against gram positive organisms. Unfortunately, linezolid resistant strains of organisms have already been reported. Tsiodras et al., Lancet, 2001, 358, 207; Gonzales et al., Lancet, 2001, 357, 1179; Zurenko et al., Proceedings Of The 39th Annual Interscience Conference On Antibacterial Agents And Chemotherapy (ICAAC); San Francisco, CA, USA , (September 26-29, 1999). Since linezolid is clinically effective and also a commercially important antibacterial agent, researchers are engaged to develop other effective linezolid derivatives.

  Despite the above, there is still a need for new anti-infective and anti-proliferative agents. In addition, since a number of anti-infective and anti-proliferative agents have utility as anti-inflammatory and prokinetic agents, there is still a need for new compounds useful as anti-infective and anti-proliferative agents. To do.

を有する、抗感染剤および／または抗増殖剤、例えば化学療法剤、抗微生物剤、抗菌剤、抗真菌剤、駆虫剤、抗ウイルス剤、抗炎症剤、および／または運動促進（胃腸管調節）剤として有用な化合物のファミリー、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを提供する。上記式中、ＡおよびＢは、フェニル、ピリジル、ピラジニル、ピリミジル、およびピリダジニルからなる群から選ばれ；Ｈｅｔ−ＣＨ_２−Ｒ^３は、式：

からなる群から選ばれ；Ｌは、場合により置換されたＣ_１〜６アルキル基であり；Ｘは、−ＮＲ^４−、−ＮＲ^４ＮＲ^４−、または−Ｓ−であり；Ｍは、式：

を有し；そして、変数Ｌ^１、Ｌ^２、Ｒ^１、Ｒ^２、Ｒ^３、Ｑ、ｍおよびｎは、詳細な記載中で以下に定義する化学的な部分または整数のそれぞれの群から選ばれる。 (Summary of Invention)
The present invention has the formula:

Anti-infective and / or anti-proliferative agents, such as chemotherapeutic agents, antimicrobial agents, antibacterial agents, antifungal agents, anthelmintic agents, antiviral agents, anti-inflammatory agents, and / or prokinetic (gastrointestinal tract regulation) Provided are a family of compounds useful as agents, or pharmaceutically acceptable salts, esters or prodrugs thereof. Wherein A and B are selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidyl, and pyridazinyl; Het-CH ₂ -R ³ is represented by the formula:

L is an optionally substituted C _1-6 alkyl group; X is —NR ⁴ —, —NR ⁴ NR ⁴ —, or —S—; M is a group selected from the group consisting of: :

And the variables L ¹ , L ² , R ¹ , R ² , R ³ , Q, m and n are selected from each group of chemical moieties or integers as defined below in the detailed description. It is.

で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグをを含み、ここで、上記式中、Ａ、Ｌ、Ｍ、Ｘ、Ｒ^１、Ｒ^３、およびｍは、詳細な記載中で以下に定義する化学的な部分または整数のそれぞれの群から選ばれる。 Some embodiments of the compounds of the invention have the formula:

Or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, L, M, X, R ¹ , R ³ , and m are detailed Selected from the respective group of chemical moieties or integers defined below in the description.

  In addition, the present invention provides a method for producing the above compounds. According to the method of manufacture, an effective amount of one or more of the compounds is administered as an anticancer agent, antimicrobial agent, antibiotic, antifungal agent, anthelmintic agent or antiviral agent, or as a proliferative disease, inflammatory disease or gastrointestinal motility For use to treat a disorder, it can be formulated with a pharmaceutically acceptable carrier for administration to a mammal. The compound or formulation can be administered, for example, by oral, parenteral, or topical route to provide an effective amount of the compound to a mammal.

  These and other aspects and embodiments of the present invention can be more fully understood by reference to the following detailed description and claims.

(Detailed description of the invention)
The present invention provides a family of compounds that can be used as anti-proliferative and / or anti-infective agents. The compound can be used, for example, as an anticancer agent, antimicrobial agent, antibacterial agent, antifungal agent, anthelmintic agent and / or antiviral agent, but is not limited thereto. In addition, the present invention provides anti-inflammatory agents (eg, used in treating chronic inflammatory airway diseases) and / or motility agents (eg, gastrointestinal motility disorders (eg, gastroesophageal reflux disease, gastric failure) Provided is a family of compounds that can be used (but not limited to) in treating paralysis (diabetic and post-operative), irritable bowel syndrome and constipation).

1. Definitions As used herein, the term “substituted” refers to any atom on a specified atom provided that the normal valence of the specified atom is not exceeded and the substitution provides a stable compound. It is meant that one or more atoms are replaced by an option from the group indicated. When the substituent is keto (ie, ═O), then two hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, an intracyclic double bond is a double bond formed between two adjacent ring atoms (eg, C = C, C = N, or N = N).

  The present invention is meant to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Non-limiting examples of common isotopes of hydrogen include tritium and deuterium, and carbon isotopes include C-13 and C-14.

  The compounds described herein can have asymmetric centers. Compounds of the invention that contain asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for producing optically active forms (eg, resolution of racemic forms or production from optically active starting materials) are well known in the art. Numerous geometric isomers such as olefins, C═N double bonds, etc. can also be present in the compounds described herein, and all of these stable isomers are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. Unless specifically specific stereochemical or isomeric forms are specifically indicated, all chiral, diastereomeric, racemic and geometric isomer forms of a structure are contemplated. All processes used to make the compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomeric forms of the compounds shown or described are also considered to be part of this invention.

When any variable (eg, R ¹ ) occurs one or more times in any constituent or formula in a compound, its definition in each case is distinct from its definition in every other occurrence. is there. Thus, for example, when a group is shown to be substituted with 0 to 2 R ¹ moieties, the group can optionally be substituted with up to 2 R ¹ moieties, and each R ¹ is a group of R ¹ Selected independently of definition. Also, combinations of substituents and / or variables can be tolerated, but only those combinations give stable compounds.

  If a bond with a substituent indicates that it crosses a bond connecting two atoms in the ring, then the substituent can be bonded to any atom in the ring. When a substituent is exemplified without an atom (thus the substituent binds to the rest of the compound of the formula shown), the substituent is bound by any atom in the substituent. be able to. Combinations of substituents and / or variables can be tolerated, but only if those combinations provide a stable compound.

Compounds of the invention containing nitrogen can be converted to N-oxides by treatment with an oxidizing agent such as 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide to produce other compounds of the invention Can be obtained. Thus, all shown and claimed nitrogen-containing compounds are shown as the indicated compound and its N-oxide derivative (this is indicated as N → O or N ⁺ -O ⁻ ) where valence and structure are permissible. Can be considered both). Moreover, in other cases, nitrogen in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidizing a parent amine with an oxidizing agent (eg, m-CPBA). All shown and claimed nitrogen-containing compounds also have the indicated compounds and their N-hydroxy (ie, N—OH) and N-alkoxy (ie, N—OR, if valence and structure are permissible). Where R is a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _3-14 carbocycle, or 3-14 membered heterocycle). We think that it includes.

Where an atom or chemical moiety is accompanied by a subscripted numerical range (e.g., _C1-6 ), the present invention is meant to encompass each numerical value within that range, as well as all intermediate ranges. For example, “C _1-6 alkyl” is 1, 2, 3, 4, 5, 6, _{1-6, 1-5,} 1-4, 1-3, 1-2, 2-6, 2- It is intended to include alkyl groups having 5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.

“Alkyl” as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C _1-6 alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl. .

As used herein, “alkenyl” refers to either a linear or branched arrangement having one or more carbon-carbon double bonds present at any stable position along the chain. It is intended to include hydrocarbon chains. For example, C _2-6 alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

As used herein, “alkynyl” refers to carbonization in either a straight chain or branched configuration with one or more carbon-carbon triple bonds present at any stable position along the chain. Intended to contain hydrogen chains. For example, C _2-6 alkenyl is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkynyl groups. Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

  As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, and iodo. “Counterion” is used to indicate a small negatively charged species (eg, chloride, bromide, hydroxide, acetate, and sulfate).

As used herein, “carbocycle” or “carbocyclic ring” refers to any stable monocyclic, bicyclic, or tricyclic ring having a specific number of carbons, any of which are It can be saturated, unsaturated or aromatic). For example, a C _3-14 carbocycle means a monocyclic, bicyclic, or tricyclic having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. I intend. Examples of carbocycles include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, Including but not limited to indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, such as [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, and [2.2.2]. ] Contains bicyclooctane. A bridged ring occurs when one or more carbon atoms are connected to two non-adjacent carbon atoms. Preferred bridges are 1 or 2 carbon atoms. Note that bridging always converts a single ring to a tricycle. If the ring is bridged, substituents described for the ring may also be present on the bridge. Also included are fused (eg, naphthyl and tetrahydronaphthyl) and spiro rings.

As used herein, the term “heterocycle” or “heterocycle” refers to one or more endocyclic heteroatoms that are saturated, unsaturated or aromatic and selected from the group consisting of nitrogen, oxygen and sulfur. (For example, 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms), including any stable monocyclic, bicyclic, or tricyclic Intended. Bicyclic or tricyclic heterocycles can have one or more heteroatoms in one ring, or the heteroatoms can be present in one or more rings. The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N → O, and S (O) _p , where p = 1 or 2). When a nitrogen atom is included in the ring, it is either N or NH (ie it maintains the trivalence of the nitrogen atom, depending on whether it is attached to a double bond in the ring) Hydrogen is present if necessary). The nitrogen atom can be substituted or unsubstituted (ie, N or NR where R is H or another substituent as defined). The heterocycle can be attached to its pendant group on any heteroatom or carbon atom to give a stable structure. The heterocycle described herein can be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, it is preferred that these heteroatoms are not adjacent to one another. Bridged rings are also included in the definition of heterocycle. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) are connected to two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. Note that bridging always converts a single ring to a tricycle. If the ring is bridged, substituents described for the ring may also be present on the bridge. Also included are spiro and fused rings.

The term “aromatic heterocycle” or “heteroaryl” as used herein refers to a stable 5, 6 or 7-membered mono- or bicyclic aromatic heterocycle, or 7, 8, 9, 10, 11 or 12-membered bicyclic aromatic heterocycles, which are carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur (eg 1 , 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms). In the case of a bicyclic heteroaromatic ring, both cases are possible (eg quinoline), but only one of the two rings is aromatic (eg 2,3-dihydroindole) It is necessary to be. The second ring can also be fused or bridged as defined above for the heterocycle. The nitrogen atom can be substituted or unsubstituted (ie, N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (ie, N → O and S (O) _p , where p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1.

  Examples of heterocycles include acridinyl, azosinyl, benzoimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl , Benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b Tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isathionyl, isobenzoph Nyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthalidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenazinyl, phenothiazinyl, phenoxatinyl, phenoxazinyl, Phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, Zolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran, tetrahydroiso Quinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -Thiadiazolyl, thianthryl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-tria Lil, 1,3,4-triazolyl, and including xanthenyl, without limitation.

  As used herein, the term “pharmaceutically acceptable” is used in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications. Means a compound, substance, composition, carrier and / or dosage form that is appropriate to do and is within the scope of normal medical judgment, balanced with a reasonable benefit / risk ratio.

  As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound wherein the parent compound is modified by forming its acid or base salt. Pharmaceutically acceptable salts include, for example, salts of mineral or organic acids of basic residues (eg amines, alkalis) or organic salts of acidic residues (eg carboxylic acids), etc. It is not limited to. The pharmaceutically acceptable salts include the usual non-toxic salts or quaternary ammonium salts of the parent compound formed (eg, non-toxic inorganic or organic acids). For example, the normal non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids. Here, the acid is 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid. , Fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid , Hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, Oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propion , Salicylic acid, stearic acid, Subaseto acid (subacetic), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, selected tartaric, and toluenesulfonic acid.

  The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Usually, the salt is a free acid or base of these compounds in water or an organic solvent or a mixture of the two (usually a non-aqueous medium, preferably ether, ethyl acetate, ethanol, isopropanol, or acetonitrile). The form can be prepared by reacting with a fixed amount of a suitable base or acid. A list of suitable salts is known in Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, 1990).

  Because prodrugs are known to increase a number of desirable properties of a drug (eg, solubility, bioavailability, ease of manufacture), the compounds of the invention can be delivered in prodrug form. Accordingly, the present invention is intended to encompass prodrugs of the compounds claimed in the present invention, methods of delivery of the same, and compositions containing the same. “Prodrug” is intended to include any covalently bonded carrier that releases an active parent drug of the invention in vivo when the prodrug is administered to a mammalian subject. The prodrugs of this invention are made by modifying functional groups present in the compound in such a way that the modification is cleaved, either routinely or in vivo, to become the parent compound. A prodrug is any hydroxy, amino, or sulfhydryl group that is cleaved to yield a free hydroxyl group, free amino group, or free sulfhydryl group, respectively, when the prodrug of the invention is administered to a mammalian subject. A compound of the present invention bonded to such a group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

  “Stable compounds” and “stable structures” are robust enough to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent It is intended to mean a compound.

  As used herein, “treat” or “treatment” means treatment of a disease state in a mammal (particularly a human) and includes: (a) a mammal (particularly the mammal). Prevention of a disease state that occurs in the disease state but is not previously diagnosed as having it; (b) suppression of the disease state (ie, suppression of its onset); and / or (C) alleviating the disease state (ie, causing a regression of the disease state).

  As used herein, “mammal” refers to human and non-human patients.

  As used herein, the term “effective amount” refers to an amount of a compound of the invention or a combination of compounds that is effective when administered alone or in combination with an anti-proliferative and / or anti-infective agent. Means. The combination of compounds is preferably a synergistic combination. For example, the synergy described by Chou and Talalay, Adv. Enzyme Regul. 1984, 22: 27-55 is such that when administered in combination, the effect of the compound when administered alone as a single agent. Greater than the additive effect of the compound. Usually, the synergistic effect is almost clearly demonstrated at suboptimal concentrations of the compound. Synergy can increase the anti-proliferative and / or anti-infective effects, or some other beneficial effect of the combination compared to the individual components, in terms of lower cytotoxicity.

  All percentages and ratios used herein are by weight unless otherwise specified.

  In the description that the composition has, includes, or contains unique components, it is also contemplated that the composition consists essentially of or consists of the described components. Similarly, where a process is described as having, including, or containing a particular process step, the process consists essentially of or consists of the described process step. Further, it should be understood that the order of steps or order for performing particular actions is immaterial so long as the invention remains operable. In addition, two or more steps or actions can be performed simultaneously.

で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを提供する。ここで、上記式中、
Ａは、フェニル、ピリジル、ピラジニル、ピリミジニル、およびピリダジニルからなる群から選ばれ;
Ｂは、フェニル、ピリジル、ピラジニル、ピリミジニル、およびピリダジニルからなる群から選ばれ；
Ｈｅｔ-ＣＨ_２-Ｒ^３は、式：

からなる群から選ばれ；
Ｍは、式：

（式中、
Ｌ^１は、結合、または場合により１個以上のＲ^４基で置換されたＣ_１〜６アルキルであり；
Ｌ^２は、結合、または場合により１個以上のＲ^４基で置換されたＣ_１〜６アルキルであり；
Ｑは、ａ）Ｈ、ｂ）−ＮＲ^４Ｒ^４、ｃ）−ＯＲ^４、およびｄ）場合により１個以上のＲ^４基で置換されたＣ_１〜６アルキルからなる群から選ばれ；そして、
Ｗは、ＯおよびＳからなる群から選ばれる）
を有し；
Ｘは、ａ）−ＮＲ^４−、ｂ）−ＮＲ^４ＮＲ^４−、およびｃ）−Ｓ−からなる群から選ばれ；
Ｌは、場合により１個以上のＲ^４基で置換されたＣ_１〜６アルキルであり；
各Ｒ^１は独立して、
ａ）Ｆ、ｂ）Ｃｌ、ｃ）Ｂｒ、ｄ）Ｉ、ｅ）−ＣＦ_３、ｆ）−ＯＲ^７、ｇ）−ＣＮ、ｈ）−ＮＯ_２、ｉ）−ＮＲ^７Ｒ^７、ｊ）−Ｃ(Ｏ)Ｒ^７、ｋ）−Ｃ(Ｏ)ＯＲ^７、ｌ）−ＯＣ(Ｏ)Ｒ^７、ｍ）−Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｎ）−ＮＲ^７Ｃ(Ｏ)Ｒ^７、ｏ）−ＯＣ(Ｏ)ＮＲ^７Ｒ^７、ｐ）−ＮＲ^７Ｃ(Ｏ)ＯＲ^７、ｑ）−ＮＲ^７Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｒ）−Ｃ(Ｓ)Ｒ^７、ｓ）−Ｃ(Ｓ)ＯＲ^７、ｔ）−ＯＣ(Ｓ)Ｒ^７、ｕ）−Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｖ）−ＮＲ^７Ｃ(Ｓ)Ｒ^７、ｗ）−ＯＣ(Ｓ)ＮＲ^７Ｒ^７、ｘ）−ＮＲ^７Ｃ(Ｓ)ＯＲ^７、ｙ）−ＮＲ^７Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｚ）−Ｃ(ＮＲ^７)Ｒ^７、ａａ）−Ｃ(ＮＲ^７)ＯＲ^７、ｂｂ）−ＯＣ(ＮＲ^７)Ｒ^７、ｃｃ）−Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ｄｄ）−ＮＲ^７Ｃ(ＮＲ^７)Ｒ^７、ｅｅ）−ＯＣ(ＮＲ^７)ＮＲ^７Ｒ^７、ｆｆ）−ＮＲ^７Ｃ(ＮＲ^７)ＯＲ^７、ｇｇ）−ＮＲ^７Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ｈｈ）−Ｓ(Ｏ)_ｐＲ^７、ｉｉ）−ＳＯ_２ＮＲ^７Ｒ^７、およびｊｊ）Ｒ^７
からなる群から選ばれ；
各Ｒ^２は独立して、
ａ）Ｆ、ｂ）Ｃｌ、ｃ）Ｂｒ、ｄ）Ｉ、ｅ）−ＣＦ_３、ｆ）−ＯＲ^７、ｇ）−ＣＮ、ｈ）−ＮＯ_２、ｉ）−ＮＲ^７Ｒ^７、ｊ）−Ｃ(Ｏ)Ｒ^７、ｋ）−Ｃ(Ｏ)ＯＲ^７、ｌ）−ＯＣ(Ｏ)Ｒ^７、ｍ）−Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｎ）−ＮＲ^７Ｃ(Ｏ)Ｒ^７、ｏ）−ＯＣ(Ｏ)ＮＲ^７Ｒ^７、ｐ）−ＮＲ^７Ｃ(Ｏ)ＯＲ^７、ｑ）−ＮＲ^７Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｒ）−Ｃ(Ｓ)Ｒ^７、ｓ）−Ｃ(Ｓ)ＯＲ^７、ｔ）−ＯＣ(Ｓ)Ｒ^７、ｕ）−Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｖ）−ＮＲ^７Ｃ(Ｓ)Ｒ^７、ｗ）−ＯＣ(Ｓ)ＮＲ^７Ｒ^７、ｘ）−ＮＲ^７Ｃ(Ｓ)ＯＲ^７、ｙ）−ＮＲ^７Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｚ）−Ｃ(ＮＲ^７)Ｒ^７、ａａ）−Ｃ(ＮＲ^７)ＯＲ^７、ｂｂ）−ＯＣ(ＮＲ^７)Ｒ^７、ｃｃ）−Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ｄｄ）−ＮＲ^７Ｃ(ＮＲ^７)Ｒ^７、ｅｅ）−ＯＣ(ＮＲ^７)ＮＲ^７Ｒ^７、ｆｆ）−ＮＲ^７Ｃ(ＮＲ^７)ＯＲ^７、ｇｇ）−ＮＲ^７Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ｈｈ）−Ｓ(Ｏ)_ｐＲ^７、ｉｉ）−ＳＯ_２ＮＲ^７Ｒ^７、およびｊｊ）Ｒ^７
からなる群から選ばれ；
Ｒ^３は、
ａ）−ＯＲ^７、ｂ）−ＮＲ^７Ｒ^７、ｃ）−Ｃ(Ｏ)Ｒ^７、ｄ）−Ｃ(Ｏ)ＯＲ^７、ｅ）−ＯＣ(Ｏ)Ｒ^７、ｆ）−Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｇ）−ＮＲ^７Ｃ(Ｏ)Ｒ^７、ｈ）−ＯＣ(Ｏ)ＮＲ^７Ｒ^７、ｉ）−ＮＲ^７Ｃ(Ｏ)ＯＲ^７、ｊ）−ＮＲ^７Ｃ(Ｏ)ＮＲ^７Ｒ^７、ｋ）−Ｃ(Ｓ)Ｒ^７、ｌ）−Ｃ(Ｓ)ＯＲ^７、ｍ）−ＯＣ(Ｓ)Ｒ^７、ｎ）−Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｏ）−ＮＲ^７Ｃ(Ｓ)Ｒ^７、ｐ）−ＯＣ(Ｓ)ＮＲ^７Ｒ^７、ｑ）−ＮＲ^７Ｃ(Ｓ)ＯＲ^７、ｒ）−ＮＲ^７Ｃ(Ｓ)ＮＲ^７Ｒ^７、ｓ）−Ｃ(ＮＲ^７)Ｒ^７、ｔ）−Ｃ(ＮＲ^７)ＯＲ^７、ｕ）−ＯＣ(ＮＲ^７)Ｒ^７、ｖ）−Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ｗ）−ＮＲ^７Ｃ(ＮＲ^７)Ｒ^７、ｘ）−ＯＣ(ＮＲ^７)ＮＲ^７Ｒ^７、ｙ）−ＮＲ^７Ｃ(ＮＲ^７)ＯＲ^７、ｚ）−ＮＲ^７Ｃ(ＮＲ^７)ＮＲ^７Ｒ^７、ａａ）−Ｓ(Ｏ)_ｐＲ^７、ｂｂ）−ＳＯ_２ＮＲ^７Ｒ^７、およびｃｃ）Ｒ^７
からなる群から選ばれ；
各Ｒ^４は独立して、
ａ）Ｈ、ｂ）＝Ｏ、ｃ）＝Ｓ、ｄ）＝ＮＲ^５、ｅ）＝ＮＯＲ^５、ｆ）＝Ｎ−ＮＲ^５Ｒ^５、ｇ）−ＯＲ^５、ｈ）−ＮＯ_２、ｉ）−ＮＲ^５Ｒ^５、ｊ）−Ｃ(Ｏ)Ｒ^５、ｋ）−Ｃ(Ｏ)ＯＲ^５、ｌ）−ＯＣ(Ｏ)Ｒ^５、ｍ）−Ｃ(Ｏ)ＮＲ^５Ｒ^５、ｎ）−ＮＲ^５Ｃ(Ｏ)Ｒ^５、ｏ）−ＯＣ(Ｏ)ＮＲ^５Ｒ^５、ｐ）−ＮＲ^５Ｃ(Ｏ)ＯＲ^５、ｑ）−ＮＲ^５Ｃ(Ｏ)ＮＲ^５Ｒ^５、ｒ）−Ｃ(Ｓ)Ｒ^５、ｓ）−Ｃ(Ｓ)ＯＲ^５、ｔ）−ＯＣ(Ｓ)Ｒ^５、ｕ）−Ｃ(Ｓ)ＮＲ^５Ｒ^５、ｖ）−ＮＲ^５Ｃ(Ｓ)Ｒ^５、ｗ）−ＯＣ(Ｓ)ＮＲ^５Ｒ^５、ｘ）−Ｒ^５Ｃ(Ｓ)ＯＲ^５、ｙ）−ＮＲ^５Ｃ(Ｓ)ＮＲ^５Ｒ^５、ｚ）−Ｃ(ＮＲ^５)Ｒ^５、ａａ）−Ｃ(ＮＲ^５)ＯＲ^５、ｂｂ）−ＯＣ(ＮＲ^５)Ｒ^５、ｃｃ）−Ｃ(ＮＲ^５)ＮＲ^５Ｒ^５、ｄｄ）−ＮＲ^５Ｃ(ＮＲ^５)Ｒ^５、ｅｅ）−ＯＣ(ＮＲ^５)ＮＲ^５Ｒ^５、ｆｆ）−ＮＲ^５Ｃ(ＮＲ^５)ＯＲ^５、ｇｇ）−ＮＲ^５Ｃ(ＮＲ^５)ＮＲ^５Ｒ^５、ｈｈ）−Ｓ(Ｏ)_ｐＲ^５、およびｉｉ）Ｒ^５
からなる群から選ばれ；
各Ｒ^５は独立して、
ａ）Ｈ、ｂ）Ｃ_１〜６アルキル、ｃ）−Ｃ(Ｏ)−Ｃ_１〜６アルキル、およびｄ）−Ｃ(Ｏ)Ｏ−Ｃ_１〜６アルキルからなる群から選ばれ、ここで、ｂ）〜ｄ）のいずれかは場合により１個以上のＲ^６基で置換され；
各Ｒ^６は独立して、
ａ）−ＯＨ、ｂ）−ＯＣ_１〜６アルキル、ｃ）−ＳＨ、ｄ）−ＮＯ_２、ｅ）−ＮＨ_２、ｆ）−ＮＨＣ_１〜６アルキル、ｇ）−Ｎ(Ｃ_１〜６アルキル)_２、ｈ）−Ｃ(Ｏ)Ｈ、ｉ）−Ｃ(Ｏ)ＯＨ、ｊ）−Ｃ(Ｏ)Ｃ_１〜６アルキル、ｋ）−ＯＣ(Ｏ)Ｃ_１〜６アルキル、ｌ）−Ｃ(Ｏ)ＯＣ_１〜６アルキル、ｍ）−Ｃ(Ｏ)ＮＨ_２、ｎ）−Ｃ(Ｏ)ＮＨＣ_１〜６アルキル、ｏ）−Ｃ(Ｏ)Ｎ(Ｃ_１〜６アルキル)_２、ｐ）−ＮＨＣ(Ｏ)Ｃ_１〜６アルキル、およびｑ）−Ｓ(Ｏ)_ｐＣ_１〜６アルキル
からなる群から選ばれ；
各Ｒ^７は独立して、
ａ）Ｈ、ｂ）Ｃ_１〜６アルキル、ｃ）Ｃ_２〜６アルケニル、ｄ）Ｃ_２〜６アルキニル、ｅ）Ｃ_３〜１４の飽和、不飽和もしくは芳香族の炭素環、ｆ）窒素、酸素および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する３〜１４員の飽和、不飽和もしくは芳香族ヘテロ環、ｇ）−Ｃ(Ｏ)−Ｃ_１〜６アルキル、ｈ）−Ｃ(Ｏ)−Ｃ_２〜６アルケニル、ｉ）−Ｃ(Ｏ)−Ｃ_２〜６アルキニル、ｊ）−Ｃ(Ｏ)−Ｃ_３〜１４の飽和、不飽和もしくは芳香族の炭素環、ｋ）窒素、酸素および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する−Ｃ(Ｏ)−３〜１４員の飽和、不飽和もしくは芳香族のヘテロ環、ｌ）−Ｃ(Ｏ)Ｏ−Ｃ_１〜６アルキル、ｍ）−Ｃ(Ｏ)Ｏ−Ｃ_２〜６アルケニル、ｎ）−Ｃ(Ｏ)Ｏ−Ｃ_２〜６アルキニル、ｏ）−Ｃ(Ｏ)Ｏ−Ｃ_３〜１４の飽和、不飽和もしくは芳香族の炭素環、およびｐ）窒素、酸素、および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する−Ｃ(Ｏ)Ｏ−３〜１４員の飽和、不飽和もしくは芳香族ヘテロ環
からなる群から選ばれ、ここで、ｂ）〜ｐ）のいずれかは場合により１個以上のＲ^８基で置換され；
各Ｒ^８は独立して、
ａ）Ｆ、ｂ）Ｃｌ、ｃ）Ｂｒ、ｄ）Ｉ、ｅ）＝Ｏ、ｆ）＝Ｓ、ｇ）＝ＮＲ^９、ｈ）＝ＮＯＲ^９、ｉ）＝Ｎ−ＮＲ^９Ｒ^９、ｊ）−ＣＦ_３、ｋ）−ＯＲ^９、ｌ）−ＣＮ、ｍ）−ＮＯ_２、ｎ）−ＮＲ^９Ｒ^９、ｏ）−Ｃ(Ｏ)Ｒ^９、ｐ）−Ｃ(Ｏ)ＯＲ^９、ｑ）−ＯＣ(Ｏ)Ｒ^９、ｒ）−(Ｏ)ＮＲ^９Ｒ^９、ｓ）−ＮＲ^９Ｃ(Ｏ)Ｒ^９、ｔ）−ＯＣ(Ｏ)ＮＲ^９Ｒ^９、ｕ）−ＮＲ^９Ｃ(Ｏ)ＯＲ^９、ｖ）−ＮＲ^９Ｃ(Ｏ)ＮＲ^９Ｒ^９、ｗ）−Ｃ(Ｓ)Ｒ^９、ｘ）−Ｃ(Ｓ)ＯＲ^９、ｙ）−ＯＣ(Ｓ)Ｒ^９、ｚ）−Ｃ(Ｓ)ＮＲ^９Ｒ^９、ａａ）−ＮＲ^９Ｃ(Ｓ)Ｒ^９、ｂｂ）−ＯＣ(Ｓ)ＮＲ^９Ｒ^９、ｃｃ）−ＮＲ^９Ｃ(Ｓ)ＯＲ^９、ｄｄ）−ＮＲ^９Ｃ(Ｓ)ＮＲ^９Ｒ^９、ｅｅ）−Ｃ(ＮＲ^９)Ｒ^９、ｆｆ）−Ｃ(ＮＲ^９)ＯＲ^９、ｇｇ）−ＯＣ(ＮＲ^９)Ｒ^９、ｈｈ）−Ｃ(ＮＲ^９)ＮＲ^９Ｒ^９、ｉｉ）−ＮＲ^９Ｃ(ＮＲ^９)Ｒ^９、ｊｊ）−ＯＣ(ＮＲ^９)ＮＲ^９Ｒ^９、ｋｋ）−ＮＲ^９Ｃ(ＮＲ^９)ＯＲ^９、ｌｌ）−ＮＲ^９Ｃ(ＮＲ^９)ＮＲ^９Ｒ^９、ｍｍ）−Ｓ(Ｏ)_ｐＲ^９、ｎｎ）−ＳＯ_２ＮＲ^９Ｒ^９、およびｏｏ）Ｒ^９
からなる群から選ばれ、
各Ｒ^９は独立して、
ａ）Ｈ、ｂ）Ｃ_１〜６アルキル、ｃ）Ｃ_２〜６アルケニル、ｄ）Ｃ_２〜６アルキニル、ｅ）Ｃ３〜１４の飽和、不飽和もしくは芳香族の炭素環、ｆ）窒素、酸素および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する３〜１４員の飽和、不飽和もしくは芳香族のヘテロ環、ｇ）−Ｃ(Ｏ)−Ｃ_１〜６アルキル、ｈ）−Ｃ(Ｏ)−Ｃ_２〜６アルケニル、ｉ）−Ｃ(Ｏ)−Ｃ_２〜６アルキニル、ｊ）−Ｃ(Ｏ)−Ｃ_３〜１４の飽和、不飽和もしくは芳香族の炭素環、ｋ）窒素、酸素および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する−Ｃ(Ｏ)−３〜１４員の飽和、不飽和もしくは芳香族のヘテロ環、ｌ）−Ｃ(Ｏ)Ｏ−Ｃ_１〜６アルキル、ｍ）−Ｃ(Ｏ)Ｏ−Ｃ_２〜６アルケニル、ｎ）−Ｃ(Ｏ)Ｏ−Ｃ２〜６アルキニル、ｏ）−Ｃ(Ｏ)Ｏ−Ｃ３〜１４飽和、不飽和もしくは芳香族の炭素環、および、ｐ）窒素、酸素および硫黄からなる群から選ばれる１個以上のヘテロ原子を含有する、−Ｃ(Ｏ)Ｏ−３〜１４員の飽和、不飽和もしくは芳香族ヘテロ環
からなる群から選ばれ、ここで、ｂ）〜ｐ）のいずれかは場合により、
ａ）Ｆ、ｂ）Ｃｌ、ｃ）Ｂｒ、ｄ）Ｉ、ｅ）−ＣＦ_３、ｆ）−ＯＨ、ｇ）−ＯＣ_１〜６アルキル、ｈ）−ＳＨ、ｉ）−ＳＣ_１〜６アルキル、ｊ）−ＣＮ、ｋ）−ＮＯ_２、ｌ）−ＮＨ_２、ｍ）−ＮＨＣ_１〜６アルキル、ｎ）−Ｎ(Ｃ_１〜６アルキル)_２、ｏ）−Ｃ(Ｏ)Ｃ_１〜６アルキル、ｐ）−ＯＣ(Ｏ)Ｃ_１〜６アルキル、ｑ）−Ｃ(Ｏ)ＯＣ_１〜６アルキル、ｒ）−Ｃ(Ｏ)ＮＨ_２、ｓ）−Ｃ(Ｏ)ＮＨＣ_１〜６アルキル、ｔ）−Ｃ(Ｏ)Ｎ(Ｃ_１〜６アルキル)_２、ｕ）−ＮＨＣ(Ｏ)Ｃ_１〜６アルキル、ｖ）−ＳＯ_２ＮＨ_２−、ｗ）−ＳＯ_２ＮＨＣ_１〜６アルキル、ｘ）−ＳＯ_２Ｎ(Ｃ_１〜６アルキル)_２、およびｙ）−Ｓ(Ｏ)_ｐＣ_１〜６アルキルからなる群から選ばれる１個以上の部分で置換され；
ｍは、０、１、２、３、または４であり；
ｎは、０、１、２、３、または４であり；そして、
各ｐは独立して０、１、または２であり；
但し、該化合物は、式：

からなる群から選ばれる式を有しない。 2. Compounds of the Invention In one embodiment, the present invention provides compounds of the formula:

Or a pharmaceutically acceptable salt, ester or prodrug thereof. Here, in the above formula,
A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
Het-CH ₂ -R ³ has the formula:

Selected from the group consisting of:
M is the formula:

(Where
L ¹ is a bond, or C _1-6 alkyl, optionally substituted with one or more R ⁴ groups;
L ² is a bond, or C _1-6 alkyl, optionally substituted with one or more R ⁴ groups;
Q is selected from the group consisting of a) H, b) —NR ⁴ R ⁴ , c) —OR ⁴ , and d) C _1-6 alkyl optionally substituted with one or more R ⁴ groups; ,
W is selected from the group consisting of O and S)
Having
X ^{is, a) -NR 4 -, b} ) -NR 4 NR 4 -, and c) is selected from the group consisting of -S-;
L is C _1-6 alkyl optionally substituted with one or more R ⁴ groups;
Each R ¹ is independently
_{a) F, b) Cl,} c) Br, d) I, e) -CF 3, f) -OR 7, g) -CN, h) -NO 2, i) -NR 7 R 7, j) - ^{C (O) R 7, k} ) -C (O) OR 7, l) -OC (O) R 7, m) -C (O) NR 7 R 7, n) -NR 7 C (O) R 7 ^{, o) -OC (O) NR} 7 R 7, p) -NR 7 C (O) OR 7, q) -NR 7 C (O) NR 7 R 7, r) -C (S) R 7, s ^{) -C (S) OR 7,} t) -OC (S) R 7, u) -C (S) NR 7 R 7, v) -NR 7 C (S) R 7, w) -OC (S) ^{NR 7 R 7, x) -NR} 7 C (S) OR 7, y) -NR 7 C (S) NR 7 R 7, z) -C (NR 7) R 7, aa) -C (NR 7) ^{OR 7, bb) -OC (NR} 7) R 7, cc) -C (NR 7) NR 7 R 7, dd) -NR 7 C (NR 7) R 7, e ^{) -OC (NR 7) NR 7} R 7, ff) -NR 7 C (NR 7) OR 7, gg) -NR 7 C (NR 7) NR 7 R 7, hh) -S (O) p R 7 _{^{, ii) -SO 2 NR 7 R}} 7, and jj) ^{R 7}
Selected from the group consisting of:
Each R ² is independently
_{a) F, b) Cl,} c) Br, d) I, e) -CF 3, f) -OR 7, g) -CN, h) -NO 2, i) -NR 7 R 7, j) - ^{C (O) R 7, k} ) -C (O) OR 7, l) -OC (O) R 7, m) -C (O) NR 7 R 7, n) -NR 7 C (O) R 7 ^{, o) -OC (O) NR} 7 R 7, p) -NR 7 C (O) OR 7, q) -NR 7 C (O) NR 7 R 7, r) -C (S) R 7, s ^{) -C (S) OR 7,} t) -OC (S) R 7, u) -C (S) NR 7 R 7, v) -NR 7 C (S) R 7, w) -OC (S) ^{NR 7 R 7, x) -NR} 7 C (S) OR 7, y) -NR 7 C (S) NR 7 R 7, z) -C (NR 7) R 7, aa) -C (NR 7) ^{OR 7, bb) -OC (NR} 7) R 7, cc) -C (NR 7) NR 7 R 7, dd) -NR 7 C (NR 7) R 7, e ^{) -OC (NR 7) NR 7} R 7, ff) -NR 7 C (NR 7) OR 7, gg) -NR 7 C (NR 7) NR 7 R 7, hh) -S (O) p R 7 _{^{, ii) -SO 2 NR 7 R}} 7, and jj) ^{R 7}
Selected from the group consisting of:
R ³ is
^{a) -OR 7, b) -NR} 7 R 7, c) -C (O) R 7, d) -C (O) OR 7, e) -OC (O) R 7, f) -C (O ^{) NR 7 R 7, g)} -NR 7 C (O) R 7, h) -OC (O) NR 7 R 7, i) -NR 7 C (O) OR 7, j) -NR 7 C (O ^{) NR 7 R 7, k)} -C (S) R 7, l) -C (S) OR 7, m) -OC (S) R 7, n) -C (S) NR 7 R 7, o) ^{-NR 7 C (S) R 7} , p) -OC (S) NR 7 R 7, q) -NR 7 C (S) OR 7, r) -NR 7 C (S) NR 7 R 7, s) ^{-C (NR 7) R 7,} t) -C (NR 7) OR 7, u) -OC (NR 7) R 7, v) -C (NR 7) NR 7 R 7, w) -NR 7 C ^{(NR 7) R 7, x} ) -OC (NR 7) NR 7 R 7, y) -NR 7 C (NR 7) OR 7, z) -NR 7 C (NR 7 ^{) NR 7 R 7, aa)} -S (O) p R 7, bb) -SO 2 NR 7 R 7 and cc) ^{R 7,}
Selected from the group consisting of:
Each R ⁴ is independently
^{a) H, b) = O} , c) = S, d) = NR 5, e) = NOR 5, f) = N-NR 5 R 5, g) -OR 5, h) -NO 2, i) ^{-NR 5 R 5, j) -C} (O) R 5, k) -C (O) OR 5, l) -OC (O) R 5, m) -C (O) NR 5 R 5, n) ^{-NR 5 C (O) R 5} , o) -OC (O) NR 5 R 5, p) -NR 5 C (O) OR 5, q) -NR 5 C (O) NR 5 R 5, r) ^{-C (S) R 5, s} ) -C (S) OR 5, t) -OC (S) R 5, u) -C (S) NR 5 R 5, v) -NR 5 C (S) R ^{5, w) -OC (S)} NR 5 R 5, x) -R 5 C (S) OR 5, y) -NR 5 C (S) NR 5 R 5, z) -C (NR 5) R 5 ^{, aa) -C (NR 5)} OR 5, bb) -OC (NR 5) R 5, cc) -C (NR 5) NR 5 R 5, dd) -NR 5 ^{(NR 5) R 5, ee} ) -OC (NR 5) NR 5 R 5, ff) -NR 5 C (NR 5) OR 5, gg) -NR 5 C (NR 5) NR 5 R 5, hh) -S (O) _p R ^5, and ii) ^{R 5}
Selected from the group consisting of:
Each R ⁵ is independently
a) H, b) C _1-6 alkyl, c) —C (O) —C _1-6 alkyl, and d) —C (O) O—C _1-6 alkyl, wherein , B) -d) are optionally substituted with one or more R ⁶ groups;
Each R ⁶ is independently
a) —OH, b) —OC _1-6 alkyl, c) —SH, d) —NO ₂ , e) —NH ₂ , f) —NHC _1-6 alkyl, g) —N (C _1-6 alkyl) ) ₂ , h) -C (O) H, i) -C (O) OH, j) -C (O) C _1-6 alkyl, k) -OC (O) C _1-6 alkyl, l)- C (O) OC _1-6 alkyl, m) -C (O) NH ₂ , n) -C (O) NHC _1-6 alkyl, o) -C (O) N (C _1-6 alkyl) ₂ , selected from the group consisting of p) -NHC (O) C _1-6 alkyl, and q) -S (O) _p C _1-6 alkyl;
Each R ⁷ is independently
a) H, b) C _1-6 alkyl, c) C _2-6 alkenyl, d) C _2-6 alkynyl, e) C _3-14 saturated, unsaturated or aromatic carbocyclic ring, f) nitrogen, saturation of oxygen and 3 to 14-membered containing one or more heteroatoms selected from the group consisting of sulfur, unsaturated or aromatic heterocyclic _{ring, g) -C (O) -C} 1~6 alkyl, h) - C (O) —C _2-6 alkenyl, i) —C (O) —C _2-6 alkynyl, j) —C (O) —C _3-14 saturated, unsaturated or aromatic carbocycle, k ) -C (O) -3 to 14-membered saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, l) -C (O) _{O-C 1 to 6 alkyl, m) -C (O) O} -C 2~6 _{alkenyl, n) -C (O) O} -C 2~6 alkynyl, o) - (O) saturated O-C _{3 to 14,} unsaturated or aromatic carbocycle, and p) a nitrogen, oxygen, and -C containing one or more heteroatoms selected from the group consisting of sulfur (O) Selected from the group consisting of O-3 to 14-membered saturated, unsaturated or aromatic heterocycles, wherein any of b) to p) is optionally substituted with one or more R ⁸ groups;
Each R ⁸ is independently
a) F, b) Cl, c) Br, d) I, e) = O, f) = S, g) = NR 9, h) = NOR 9, i) = N-NR 9 R 9, j) _{^{-CF 3, k) -OR 9,}} l) -CN, m) -NO 2, n) -NR 9 R 9, o) -C (O) R 9, p) -C (O) OR 9, q ^{) -OC (O) R 9,} r) - (O) NR 9 R 9, s) -NR 9 C (O) R 9, t) -OC (O) NR 9 R 9, u) -NR 9 C ^{(O) OR 9, v)} -NR 9 C (O) NR 9 R 9, w) -C (S) R 9, x) -C (S) OR 9, y) -OC (S) R 9, ^{z) -C (S) NR 9} R 9, aa) -NR 9 C (S) R 9, bb) -OC (S) NR 9 R 9, cc) -NR 9 C (S) OR 9, dd) ^{-NR 9 C (S) NR 9} R 9, ee) -C (NR 9) R 9, ff) -C (NR 9) OR 9, gg) -OC ^{(NR 9) R 9, hh} ) -C (NR 9) NR 9 R 9, ii) -NR 9 C (NR 9) R 9, jj) -OC (NR 9) NR 9 R 9, kk) -NR ⁹ C (NR ⁹ ) OR ⁹ , ll) -NR ⁹ C (NR ⁹ ) NR ⁹ R ⁹ , mm) -S (O) _p R ⁹ , nn) -SO ₂ NR ⁹ R ⁹ , and oo) R ⁹
Selected from the group consisting of
Each R ⁹ is independently
_{a) H, b) C} 1~6 alkyl, _{c) C 2 to 6} alkenyl, _{d) C 2 to 6} alkynyl, e) saturated C3～14, unsaturated or aromatic carbocycle, f) nitrogen, oxygen and saturated 3 to 14 membered containing one or more heteroatoms selected from the group consisting of sulfur, unsaturated or aromatic _{heterocycle, g) -C (O) -C} 1~6 alkyl, h) - C (O) —C _2-6 alkenyl, i) —C (O) —C _2-6 alkynyl, j) —C (O) —C _3-14 saturated, unsaturated or aromatic carbocycle, k ) -C (O) -3 to 14-membered saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, l) -C (O) _{O-C 1 to 6 alkyl, m) -C (O) O} -C 2~6 alkenyl, n) -C (O) O -C2~6 alkynyl, o) - C (O) O—C 3-14 containing a saturated, unsaturated or aromatic carbocycle, and p) one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, —C (O) Selected from the group consisting of O-3-14 membered saturated, unsaturated or aromatic heterocycles, wherein any of b) -p) is optionally
a) F, b) Cl, c) Br, d) I, e) -CF 3, f) -OH, g) -OC 1~6 _{alkyl, h) -SH, i) -SC} 1~6 alkyl, _{j) -CN, k) -NO 2} , l) -NH 2, m) -NHC 1~6 _alkyl, n) -N _(C 1~6 _{alkyl) 2, o) -C (O} ) C 1~6 _{alkyl, p) -OC (O) C} 1~6 _{alkyl, q) -C (O) OC} 1~6 _{alkyl, r) -C (O) NH} 2, s) -C (O) NHC 1~6 alkyl , t) -C (O) N (C 1~6 _{alkyl) 2, u) -NHC (O} ) C 1~6 _{alkyl, v) -SO 2 NH 2 -} , w) -SO 2 NHC 1~6 alkyl , x) is substituted with -SO ₂ N _{(C 1 to 6 alkyl) 2,} and y) -S (O) 1 or more moieties selected from the group consisting of _p C _{1 to 6} alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
Each p is independently 0, 1, or 2;
However, the compound has the formula:

Does not have a formula selected from the group consisting of

［式中、Ａ、Ｂ、Ｌ、Ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、ｍ、およびｎは上に定義する通りである］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。 One embodiment of the present invention is a compound of the formula:

[Wherein A, B, L, M, R ¹ , R ² , R ³ , X, m, and n are as defined above]
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

［式中、Ａ、Ｂ、Ｌ、Ｍ、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、ｍ、およびｎは上に定義する通りである］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。 Other embodiments have the formula:

[Wherein A, B, L, M, R ¹ , R ² , R ³ , X, m, and n are as defined above]
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

  A is selected from the group consisting of phenyl and pyridyl; B is selected from the group consisting of phenyl and pyridyl; m is 0, 1, or 2; and n is 0, 1, or 2 Contains a compound.

［式中、Ａ、Ｒ^２およびｎは上に定義する通りである］
である。ある実施態様において、Ａ−Ｂは、式：

［Ａは、上に記載する通りに定義する］
である。 In some embodiments, AB can have the formula:

[Wherein A, R ² and n are as defined above]
It is. In some embodiments, AB can have the formula:

[A is defined as described above]
It is.

［式中、Ｂは上に記載する通りに定義する］
である。 In various embodiments, AB has the formula:

[Wherein B is defined as described above]
It is.

である。 In some embodiments, R ³ is —NHC (O) R ⁷ . The compounds described in these embodiments include those where R ⁷ is —CH ₃ . In another embodiment, R ³ is of the formula:

It is.

［式中、Ａ、Ｂ、Ｌ、Ｍ、Ｒ^１、Ｒ^２、Ｘ、ｍおよびｎは上に記載する通りに定義する］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。 An embodiment of the present invention has the formula:

[Wherein A, B, L, M, R ¹ , R ² , X, m and n are defined as described above]
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

［式中、Ａ、Ｌ、Ｍ、Ｒ^１、Ｒ^３、Ｘ、およびｍは上に記載する通りに定義する］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。これらの実施態様に記載する化合物は、式：

［式中、Ａ、Ｌ、Ｍ、Ｒ^１、Ｘ、およびｍは上に記載する通りに定義する］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。 Another embodiment of the present invention is a compound of the formula:

[Wherein A, L, M, R ¹ , R ³ , X, and m are defined as described above]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. The compounds described in these embodiments have the formula:

Wherein A, L, M, R ¹ , X, and m are defined as described above.
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

［式中、Ｌ、Ｍ、Ｘ、およびＲ^３は上に記載する通りに定義する］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。これらの実施態様に記載する化合物は、式：

［式中、Ｌ、ＭおよびＸは上に記載する通りに定義する］
で示される化合物、またはその医薬的に許容し得る塩、エステルもしくはプロドラッグを含む。 An embodiment of the present invention has the formula:

Wherein L, M, X, and R ³ are defined as described above.
Or a pharmaceutically acceptable salt, ester or prodrug thereof. The compounds described in these embodiments have the formula:

[Wherein L, M and X are defined as described above]
Or a pharmaceutically acceptable salt, ester or prodrug thereof.

［式中、各Ｒ^４は独立して請求項１に記載する通りに定義する］
である。これらの実施態様に記載する化合物は、式：

で示される化合物を含む。 In certain embodiments, M is of the formula:

[Wherein each R ⁴ is independently defined as defined in claim 1]
It is. The compounds described in these embodiments have the formula:

The compound shown by these is included.

［式中、各Ｒ^４は独立して請求項１に記載する通りに定義する］
である。これらの実施態様に記載する化合物は、式：

で示される化合物を含む。 In another embodiment, M is of the formula:

[Wherein each R ⁴ is independently defined as defined in claim 1]
It is. The compounds described in these embodiments have the formula:

The compound shown by these is included.

である。 In certain embodiments, X is —NH—. In other embodiments, X is of the formula:

It is.

  In another aspect, the present invention provides a process for the preparation of the compounds described in the present invention. In yet another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of one or more of the above compounds and a pharmaceutically acceptable carrier. Suitable formulation agents are described in detail in item 4 herein below.

  One or more of the above compounds may also be contained in a medical device. For example, a medical device (eg, a medical stent) can include or be coated with one or more of the compounds of the present invention.

  In another aspect, the present invention provides a method of treating a microbial infection, fungal infection, viral infection, parasitic disease, proliferative disease, inflammatory disease, or gastrointestinal motility disorder in a mammal. The method includes administering a compound or one or more effective amounts of a pharmaceutical composition of the invention, eg, by oral, parenteral, or topical route.

  The present invention provides a method of treating a disease in a mammal, thereby reducing the symptoms of the disease, comprising administering to the mammal one or more effective amounts of a compound of the present invention. The disease includes skin infection, nosocomial pneumonia, pneumonia after viral infection, abdominal infection, urinary infection, bacteremia, sepsis, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis Selected from the group consisting of postoperative prophylaxis, peritoneal infection, bone infection, joint infection, methicillin resistant Staphylococcus aureus infection, vancomycin resistant enterococcal infection, linezolid resistant biological infection, and tuberculosis.

3. Confirmation of Compounds of the Invention After manufacture, compounds designed, selected and / or optimized by the methods described above can be used in the art to determine whether the compounds have biological activity. This can be confirmed using a variety of assays known to the vendor. For example, measuring whether the molecules have the expected activity, binding activity and / or binding specificity by routine assays (eg, including but not limited to the assays described below). Can be confirmed.

  Moreover, high throughput screening can be used to speed up analysis using the assay. As a result, it may be possible to rapidly screen the molecules described herein for activity (eg, anticancer, antibacterial, antifungal, anthelmintic, or antiviral agents). Also, using techniques known in the art, assay whether the compound interacts with ribosomes or subunits of ribosomes and / or is effective as a regulator (eg, inhibitor) of protein synthesis. Can be possible. General methodologies for performing high-throughput screening are described, for example, by Devlin, High-throughput screening, (Marcel Dekker, 1998); and US Pat. No. 5,763,263. High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

(1) Surface Binding Studies Various binding assays can be useful for screening new molecules for their binding activity. One method includes surface plasmon resonance (SPR), which can be used to assess the binding properties of the molecules of the invention with respect to ribosomes, ribosomal subunits, or fragments thereof.

  SPR methodology measures the interaction between two or more macromolecules in real time by the generation of quantum-mechanical surface plasmons. One device (BIAcore Biosensor RTM (Pharmacia Biosensor, Piscatawy, NJ) has a thin gold film (which serves as a disposable biosensor “chip”) and a user-adjustable buffer compartment A polychromatic light focused beam is provided at the interface between the 100 nm thick “hydrogel” (this provides a matrix for the shared immobilization of the target analysis). The plasmon resonance increases when the light collection interacts with the free electron cloud of the gold film. Is spectrally depleted at the wavelength that optimally emits the resonance, separating the reflected polychromatic lamp into its constituent wavelengths (by a prism), By measuring the depleted frequency, the via core establishes an optical interface that accurately conveys the behavior of the generated surface plasmon resonance, and when designed as described above, the plasmon resonance (and thus , The depletion spectrum) is sensitive to mass in the evanescent field, which roughly corresponds to the thickness of the hydrogel. Is immobilized on the hydrogel and the interacting partner is provided by a buffer compartment, the interaction between the two components is the accumulation of mass in the evanescent field, and the It can be measured in real time based on its corresponding effect of the plasmon resonance measured by the depletion spectrum. The system eliminates the need to label any component and allows fast and sensitive real-time measurement of the molecular interaction.

(2) Fluorescence polarization Fluorescence polarization (FP) is easily applied to protein-protein, protein-ligand, or RNA-ligand interactions to derive the IC ₅₀ and Kd of the binding reaction between two molecules. Is a measurement technique that can. In this technique, one of the molecules of the present invention is conjugated to a fluorophore. This is usually a smaller molecule (in this case, a compound of the invention) in the system. Sample mixtures containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragments thereof are excited with vertically polarized light. Light is absorbed by the probe fluorophore and the short time laser is re-emitted. The degree of polarization of the emitted light is measured. The polarization of the emission depends on several factors, but the most important is the viscosity of the solution and the apparent molecular weight of the fluorophore. In the case of appropriate controls, the change in the degree of polarization of the emission depends only on the apparent molecular weight change of the fluorophore, in other words, the probe-ligand conjugate is free in the solution. Or whether it binds to the receptor. FP-based binding assays have a number of important advantages, such as IC ₅₀ and Kd under true homogeneous equilibrium conditions, speed of analysis and comfort to automation, and cloudy suspensions and colored solutions Including the possibility to be screened in.

(3) Protein synthesis In addition to confirmation by the biochemical assay described above, the compounds of the present invention should also be identified as modulators of functional activity of ribosomes or subunits of ribosomes (eg, inhibitors of protein synthesis). I am planning to be able to.

Moreover, more specific protein synthesis inhibition assays involve administering the compound to all organisms, tissues, organs, organelles, cells, cells or intracellular extracts, or purified ribosome products, and This can be done, for example, by observing its pharmacological and inhibitory properties by measuring the inhibition constant (IC ₅₀ ) in inhibiting protein synthesis. Uptake of ³ H leucine or ³⁵ S methionine or similar experiments can be performed to study the activity of protein synthesis. A change in the amount or rate of protein synthesis in a cell in the presence of a molecule of the invention indicates that the molecule is a regulator of protein synthesis. An increase in the rate or amount of protein synthesis indicates that the molecule is an inhibitor of protein synthesis.

  Moreover, the compounds can be assayed at the cellular level for antiproliferative or anti-infective properties. For example, if the target organism is a microorganism, the activity of the compound of the invention can be assayed by growing the microorganism of interest in a medium that either contains or lacks the compound. . Inhibition of proliferation can be an indication that the molecule can act as a protein synthesis inhibitor. More specifically, the activity of the compounds of the invention against bacterial pathogens can be demonstrated by the ability of the compounds to inhibit the growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to contain a variety of target pathogenic species, some of which have been identified for resistance mechanisms. The use of these organism panels allows the measurement of structure-activity relationships not only in terms of potency and spectrum, but also in terms of avoiding resistance mechanisms in advance. The National Committee for Clinical Laboratory Standards (NCCLS) guidelines (NCCLS. M7-A5-Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. NCCLS Document M100-S12 / M7 (ISBN 1 -56238-394-9)) can be carried out in a microtiter tray according to the usual methodology published by.

4). Formulation and Administration The compounds of the present invention are useful in the prevention or treatment of various human or other animal diseases, including, for example, bacterial infections, fungal infections, viral infections, parasitic diseases, and cancer. possible. After identification, the active molecules of the invention can be included in any suitable carrier prior to use. The dose of active molecule, mode of administration and use of suitable carrier will depend on the intended recipient and target organism. Formulations for both veterinary and human medical use of the compounds described in this invention typically comprise the compound in combination with a pharmaceutically acceptable carrier.

  The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient. Pharmaceutically acceptable carriers in this regard include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and others that are compatible with pharmaceutical administration. Intended to include The use of those media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, its use in the composition is contemplated. Supplementary active compounds, which have been identified or designed according to the present invention and / or are known in the art, can also be included in the composition. The formulations can usually be provided in dosage forms and can be prepared by any of the methods well known in the pharmaceutical / microbiology field. Usually, some formulations are prepared by combining the compound with a liquid carrier or finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation.

  A pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include oral or parenteral (eg, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration). Solutions or suspensions used for parenteral, intradermal, or subcutaneous application include the following components: sterile dilutions (eg, water for injection, saline, carrier oils) ), Polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents); antibacterial agents (eg, benzyl alcohol or methyl paraben); antioxidants (eg, ascorbic acid or sodium hydrogen sulfate); chelating agents (eg, ethylenediaminetetraacetic acid) ); Buffers (eg, acetic acid, citric acid, or phosphoric acid); and agents for adjusting tonicity (eg, sodium chloride or dextrose). The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

  Useful solutions for oral or parenteral use can be prepared by any of the methods well known in the pharmaceutical art (eg, described in Remington's Pharmaceutical Sciences, 18th edition, (Mack Publishing Company, 1990)). . Formulations for parenteral administration also include glycolic acid for buccal administration, methoxysalicylic acid for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be contained in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also mix the drug with non-irritating excipients (eg, cocoa butter, other glycerides) or other components that are solid at room temperature and liquid at body temperature Can be formulated. The formulation can also include, for example, polyalkylene glycols (eg, polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalene). Formulations for direct administration can contain glycerol and other components of high viscosity. Other potentially useful parenteral carriers for these drugs include, for example, ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration may contain, for example, lactose as an excipient, or for administration in the form of nasal drops or as a nasally applied gel, for example polyoxyethylene-9-lauryl ether It can be an aqueous or oily solution containing glycolic acid and deoxycholic acid. Retention enemas can also be used for rectal delivery.

  Formulations of the present invention suitable for oral administration may be in the following forms: discrete units (eg, capsules, gelatin capsules, sachets, tablets, troches, or lozenges (each pre- A powder or granule composition; a solution or suspension in an aqueous or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. It can be administered in the form of an electuary or paste, and a tablet can be made by compressing or molding the drug, optionally with one or more accessory ingredients. Compresses the drug in a flowable form (eg powder or granules) in a suitable machine, optionally with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered drug and a suitable carrier moistened with an inert liquid diluent. Can do.

  Oral compositions usually include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions made with a liquid carrier for use as a mouthwash include the compound in a liquid carrier, which is used orally and is expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain the following ingredients or compounds of similar properties: a binder (eg, microcrystalline cellulose, gum tragacanth, or gelatin); an excipient (eg, Disintegrants (eg, alginic acid, Primogel, or corn starch); lubricants (eg, magnesium stearate, or Sterotes); glidants (eg, Colloidal silicon dioxide); sweeteners (eg, sucrose, or saccharin); or fragrances (eg, peppermint, methyl salicylate, or orange flavoring).

  Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (in this case, water soluble), or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. Including. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). As such, it should be stable under the conditions of manufacture and storage, and it should be preserved from the contaminating action of microorganisms such as bacteria or fungi. The carrier can be a solvent, or a dispersion medium, which contains, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating agent (eg, lecithin), by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Delaying agents such as aluminum monostearate and gelatin can be included in the composition.

  Sterile injectable solutions may contain the required amount of active compound in a suitable solvent together with one or a combination of the above ingredients and, if necessary, subsequently prepared by filter sterilization methods. it can. Dispersants are usually prepared by including the active compound in a sterilizing vehicle, which includes a base dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the production of sterile injectable solutions, the production process includes vacuum drying and freeze drying, whereby the active ingredient and any further desired from the sterile filtered solution described above. To obtain a powder of the ingredients.

  Formulations suitable for intra-articular administration can be in the form of a sterile aqueous formulation of the drug that can be in microcrystalline form (eg, in the form of an aqueous microcrystalline suspension). Liposomal formulations or biodegradable polymer systems can also be used to provide drugs for both intra-articular and ocular administration.

  Formulations suitable for topical administration (including ocular treatment) include liquid or semi-liquid formulations (eg, liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions (eg, , Creams, ointments, or pastes)); or solutions or suspensions (eg, drops). Formulations for topical administration to the skin surface can be prepared by dispersing the drug together with a dermatologically acceptable carrier (eg lotion, cream, ointment, or soap). . Carriers that can form a film or layer on the skin to localize application and inhibit removal are particularly useful. For topical administration to the internal tissue surface, the drug can be dispersed in liquid tissue that adheres to the tissue surface or other materials known to increase absorption into the tissue surface. For example, hydroxypropylcellulose or fibrinogen / thrombin solutions can be used to advantage. Alternatively, a tissue coating solution (eg, a pectin-containing formulation) can be used.

  For inhalation procedures, inhalation of powders (self-propelling or spray formulations) that are dispersed using a spray, nebulizers, or atomizers can be used. In the case of self-spray solutions and spray formulations, the effect is to select a valve that has the desired spray properties (ie, can provide a spray with the desired particle size), or for a sustained release particle size. It can be achieved either by containing the active ingredient as a suspended powder. The formulation may take the form of a fine powder for nasal administration from a powder inhalation device or a formulation dispersed with a self-sprayed powder. For administration by inhalation, the compounds can also be delivered in the form of an aerosol spray from a pressure resistant container or dispenser (including a suitable propellant (eg, a gas such as carbon dioxide)) or a nebulizer. it can.

  Systemic administration can also be taken by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are typically formulated into ointments, waxes, gels, or creams as commonly known in the art.

  The active compounds can be prepared with carriers that will prevent the compound from rapid elimination from the body, including, for example, sustained release formulations (including implants and microcapsule delivery systems). Biodegradable, biocompatible polymers (eg, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid) can be used. The method for producing the formulation will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art (for example, described in US Pat. No. 4,522,811).

  Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form is a physically discrete unit adapted as a unit dose for the subject being treated, each unit being combined with the required pharmaceutical carrier to produce the desired therapeutic effect Means a predetermined amount of active compound. The specifications for the dosage unit forms of the present invention depend on the specific nature of the active compound and the specific therapeutic effect to be achieved, as well as the limitations inherent in the art of formulating the active compound for the treatment of an individual. , And depend directly on these. Moreover, administration can be more continuous by periodic bolus injection or by intravenous, intramuscular, or intraperitoneal administration from an external reservoir (eg, an intravenous sac).

  Where adhesion to a tissue surface is desired, the composition may include a drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound can then be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drug is administered parenterally or orally to a human or other mammal, eg, in an effective amount (eg, an amount that provides an appropriate concentration of the drug for a time sufficient to induce the desired effect). Can be formulated for administration.

  When the active compound is used as part of a transplantation method, it can be provided to a living tissue or organ prior to removal of the tissue or organ from the donor. The compound can be provided to a donor host. Alternatively or additionally, after removal from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue by injection into the tissue, or as such is described in the specification and / or of methods and formulations known in the art. It can be provided systemically by either oral or parenteral administration using either. If the drug includes a portion of a tissue or organ preservation solution, it may be advantageous to use any commercially available preservation solution. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution, and lactate Ringer solution.

  The active compounds identified or designed by the methods described herein can be administered to an individual to treat a disease (prophylactically or therapeutically). In combination with the treatment, drug genomics (ie, a study of the relationship between an individual's genomic type and the individual's response to a foreign compound or drug) can be considered. Metabolic differences in therapeutics can result in severe toxicity or therapeutic failure by altering the correlation between doses and blood concentrations of pharmacologically active drugs. Accordingly, the physician or clinician may determine whether to administer the drug and related drug genomics in tailoring the dose and / or therapeutic regimen of treatment with the drug. You can think using the knowledge gained from your research.

  In therapeutic use to treat or combat bacterial infections in mammals, the compound or pharmaceutical composition thereof is the amount of active ingredient in an animal undergoing treatment that would be antimicrobially effective, in the blood It is administered orally, parenterally and / or topically in a dose to obtain and maintain a concentration that is at the level or level in the tissue. The term “effective amount” is sufficient for a compound of the invention to elicit biological activity (eg, antibacterial activity, antifungal activity, antiviral activity, anthelmintic activity, and / or antiproliferative activity). It is understood to mean present in or on the recipient by volume. In general, an effective amount of the active ingredient dose ranges from about 0.1 to about 100 mg / kg body weight / day, more preferably from about 1.0 to about 50 mg / kg body weight / day. The amount administered will also depend on variables (eg, disease type and size, treatment indicators, overall health of the patient, relative biological efficacy of the compound being delivered, drug formulation, formulation in the formulation). It will depend on the presence and type of form and the route of administration. The initial dose administered can be increased below the upper limit level to achieve the desired blood or tissue level quickly, or the initial dose can be lower than the optimal value, and It should be understood that the daily dose can be increased continuously during the treatment period depending on the particular situation. If desired, the daily dose can also be divided into multiple doses (eg, 2-4 times a day).

5). Examples Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker Avance 300 or Avance 500 spectrometer, or optionally a GE-Nicolet 300 spectrometer. Typical reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade and anhydrides obtained from the manufacturer unless otherwise specified. "Chromatography" or "purification with silica gel" means flash column chromatography using silica gel (EM Merck, silica gel 60, 230-400 mesh) unless otherwise specified. N- (t-butoxycarbonyl) amino acid amide was prepared according to literature procedures (eg, by Pozdnev, VF, Tetrahedron Lett. 1995, 36 (39), 7115-7118).

Exemplary compounds described in this invention are illustrated in Table 1.

  The above compounds and others can be prepared directly using conventional chemistry known and used in the art. An example of an exemplary synthetic reaction scheme is illustrated below as a non-limiting example.

Example 1-Preparation of Biaryl Precursor Scheme 1 illustrates the preparation of various biaryl intermediates useful for preparing the compounds of the present invention. The known iodoaryl oxazolidinone intermediate 1 (see US Pat. Nos. 5,523,403 and 5,565,571) was coupled with substituted aryl boronic acids (Suzuki reaction) to give biaryl alcohol 2. Mesylate 3, azide 4 and amine 5 were then prepared using chemistry well known to those skilled in the art.

Preparation of alcohol 2 Suspension of N- [3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide 1 (14.0 g, 37 mmol) in toluene (120 mL) The solution was diluted with 4- (hydroxymethyl) phenylboronic acid (7.87 g, 51.8 mmol, 1.4 eq), potassium carbonate (K ₂ CO ₃ , 15.32 g, 111 mmol, 3.0 eq), ethanol (EtOH , 40 mL) and H ₂ O (40 mL) at 25 ° C. and the resulting mixture was degassed three times at 25 ° C. under a steady stream of argon. Subsequently, tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ , 2.14 g, 1.85 mmol, 0.05 eq) is added to the reaction mixture, and the resulting reaction mixture is again degassed three times. And then heated to a gentle reflux for 6 hours. After showing that the coupling reaction was complete by thin layer chromatography (TLC) and HPLC, the reaction mixture was cooled to room temperature and then treated with H ₂ O (240 mL). The resulting mixture was then stirred at room temperature for 10 minutes, after which it was cooled to 0-5 ° C. for 1 hour. The solid precipitate was collected by filtration, washed with H ₂ O (2 × 100 mL) and 20% ethyl acetate (EtOAc) / hexane (2 × 50 mL) and dried under vacuum. Crude target N- [3- (2-fluoro- ^4' -hydroxymethyl-biphenyl-4-yl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide 2 (12.50 g, 94% yield) Was obtained as an off-white solid. This material was found to be essentially pure by HPLC and ¹ H NMR and was used directly in subsequent reactions without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.76 (s, 3H, COCH ₃ ), 3.35 (t, 2H, J = 5.4 Hz), 3.69 (dd, 1H, J = 6.4, 9.2 Hz), 4.08 (t, 1H, J = 9.1 Hz), 4.46 (d, 2H, J = 5.7 Hz, CH ₂ OH), 4.68 (m, 1H), 5.16 (t, 1H, J = 5.7 Hz, OH), 7.25- 7.52 (m, 7H, aromatic-H), 8.18 (t, 1H, J = 5.8 Hz, NHCOCH ₃ ). LCMS (ESI) m / e 359 (M + H) ⁺ .

Preparation of Mesylate ₃ A suspension of 2 (12.49 g, 34.90 mmol) in methylene chloride (CH ₂ Cl ₂ , 150 mL) was triethylamine (Et ₃ N, 7.07 g, 9.7 mL, 70 mmol, 2.0 The resulting mixture is cooled to 0-5 ° C. followed by methanesulfonyl chloride (4.80 g, 3.24 mL, 41.9 mmol, 1.2 eq). The solution was dropped at 0 to 5 ° C. The resulting reaction mixture was subsequently stirred at 0-5 ° C. for 2 hours. After TLC and HPLC showed that the reaction was complete, the reaction mixture was treated with H ₂ O (100 mL) at 0-5 ° C. The mixture was then concentrated under vacuum to remove most of the CH ₂ Cl ₂ and the resulting slurry was treated with H ₂ O (150 mL). The mixture was stirred at room temperature for 10 minutes, after which it was cooled to 0-5 ° C. for 30 minutes. The solid precipitate was collected by filtration, washed with H ₂ O (2 × 100 mL) and 20% EtOAc / hexane (2 × 50 mL) and dried under vacuum. Crude object methanesulfonic acid 4 ^'- [5- (acetylamino-methyl) - 2-oxo - oxazolidin-3-yl] ^-2' - fluoro - biphenyl-4-yl methyl ester 3 (11.84 g, 78 % Yield) was obtained as an off-white solid which was found to be essentially pure by TLC and HPLC and was used directly in the subsequent reaction without further purification. LCMS (ESI) m / e 437 (M + H) ⁺ .

Preparation of Azide 4 A solution of 3 (9.27 g, 21.26 mmol) in anhydrous N, N-dimethylformamide (DMF, 50 mL) was added to sodium azide (NaN ₃ , 5.53 g, 85.04 mmol, 4.0 eq. ) And the resulting reaction mixture was warmed to 70-80 ° C. for 4 hours. After TLC and HPLC showed that the reaction was complete, the reaction mixture was cooled to room temperature and then treated with H ₂ O (150 mL). The resulting mixture was stirred at room temperature for 10 minutes and then cooled to 0-5 ° C. for 1 hour. The solid precipitate was collected by filtration, washed with H ₂ O (2 × 100 mL) and 20% EtOAc / hexane (2 × 50 mL) and dried under vacuum. Crude object of N- [3- (4 ^'- azidomethyl-2-fluoro - diphenyl-4-yl) -2-oxo - oxazolidin-5-ylmethyl] - acetamide 4 (7.16 g, 88% yield) Obtained as an off-white solid. The material was found to be essentially pure by TLC and HPLC and was used directly in subsequent reactions without further purification. LCMS (ESI) m / e 384 (M + H) ⁺ .

Preparation of amine 5 A solution of 4 (7.16 g, 18.69 mmol) in tetrahydrofuran (THF) (100 mL) was added to triphenylphosphine (PPh ₃ , 5.88 g, 22.43 mmol, 1.2 eq) and H ₂ O. (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv.) Was used at 25 ° C. and the resulting reaction mixture was warmed to 50-55 ° C. for 12 hours. After TLC and HPLC showed that the reduction reaction was complete, the reaction mixture was cooled to room temperature, after which the solvent was removed in vacuo. The residue was purified by flash column chromatography (gradient elution of 0-15% methanol (MeOH) —CH ₂ Cl ₂ ) to yield the desired N- [3- ( ^4′ -aminomethyl- 2-Fluoro-biphenyl-4-yl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide 5 (5.82 g, 87% yield) was obtained, which was used directly in the subsequent reaction. It was sufficiently pure. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.85 (s, 3H, COCH ₃ ), 3.04 (br.s, 2H, NH ₂ ), 3.44 (t, 2H, J = 5.4 Hz), 3.78 (m , 3H), 4.18 (t, 1H, J = 9.1 Hz), 4.77 (m, 1H), 7.25-7.60 (m, 7H, aromatic-H), 8.20 (t, 1H, J = 5.8 Hz, NHCOCH ₃ ). LCMS (ESI) m / e 359 (M + 2H) ²⁺ .

方法Ａ：
無水ＣＨ_２Ｃｌ_２（２ｍＬ）、ＭｅＯＨ（２ｍＬ）およびＮ,Ｎ−ジイソプロピルエチルアミン（ヒューニッヒ塩基(Hunig's base)、２ｍＬ）中のアミン５（０．０７５ｇ、０．２１ｍｍｏｌ）およびブロモアセトアミド６（０．０３０ｇ、０．２１ｍｍｏｌ）の混合物を、８０℃で１８時間加熱した。溶媒を真空下で除去し、そして該粗生成物をシリカゲルカラム（ＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨの２０：１：０．０５〜１８：１：０．０５〜１６：１：０．０５〜１４：１：０．０５）で精製して、白色固体の化合物１０１（０．０６４ｇ、７４％）を得た。 Example 2 Preparation of Compound 101 Compound 101 was prepared from amine 5 and bromoacetamide 6 as shown in Reaction Scheme 2 below.

Method A:
Anhydrous _{CH 2 Cl 2 (2mL),} MeOH (2mL) and N, N- diisopropylethylamine (Hunig's base (Hunig's base), 2mL) solution of amine 5 (0.075 g, 0.21 mmol) and bromoacetamide 6 (0. 030 g, 0.21 mmol) was heated at 80 ° C. for 18 hours. The solvent was removed under vacuum and the crude product was purified on a silica gel column (CH ₂ Cl ₂ / MeOH / NH ₄ OH 20: 1: 0.05 to 18: 1: 0.05 to 16: 1: 0. 05-14: 1: 0.05) to give white solid compound 101 (0.064 g, 74%).

Another method for producing Compound 101 from aldehyde 7 and glycinamide hydrochloride 8 is shown in Reaction Scheme 3 below.

Method B:
To a suspension of glycinamide hydrochloride 8 (0.076 g, 0.674 mmol) and magnesium sulfate (MgSO ₄ , 0.250 g, 2.080 mmol) in MeOH (4 mL) and THF (1 mL) was added oxazolidinone aldehyde 7 ( This is prepared from iodo 1 and 4-formylboronic acid in the same manner as alcohol 2 in Example 1) (0.120 g, 0.337 mmol). The mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (NaBH (OAc) ₃ , 0.200 g, 0.940 mmol) was added and stirring was continued for 3 hours. The reaction was filtered and the solvent removed in vacuo. The crude was purified as in Method A above to give a white solid 101 (0.026 g, 19%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (t, J = 6 Hz, 1H), 7.65-7.39 (m, 7H), 7.32 (bs, 1H), 7.07 (bs, 1H), 4.76 (m, 1H), 4.17 (t, J = 9 Hz, 1H), 3.81-3.72 (m, 3H), 3.43 (t, J = 5 Hz, 2H), 3.05 (s, 2H), 1.84 (s, 3H). LCMS (ESI) m / e 415.2 (M + H) ⁺ .

化合物１０２は、最初にＢｏｃ−アランアミド(alanamide)９をＣＨ_２Ｃｌ_２中の５０％トリフルオロ酢酸（ＴＦＡ）を用いて０℃で３０分間処理することによって製造した。溶媒を真空下で除去後に、該粗Ｂｏｃ−脱保護生成物を、１０１の製造についての方法Ｂに記載する通り（ＮａＢＨ_４をヒドリド源として使用することを除く）、アルデヒド７と反応した。カラム精製（ＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨの２５：１：０．０５〜２０：１：０．０５〜１５：１：０．０５）後に、白色固体の化合物１０２を約１．４％収率で単離した。¹H-NMR (300 MHz, CDCl₃/CD₃OD) δ 7.53-7.25 (m, 7H), 4.73 (m, 1H), 4.10 (t, J = 9 Hz, 1H), 3.79-3.57 (m, 3H), 3.49 (d, J = 5 Hz, 2H), 1.88 (s, 3H), 1.20 (d, J = 7 Hz, 3H)。LCMS (ESI) m/e 429.2 (M + H)+。 Example 3-Preparation of Compound 102

Compound 102 was prepared by first treating Boc-alanamide 9 with 50% trifluoroacetic acid (TFA) in CH ₂ Cl ₂ at 0 ° C. for 30 minutes. After removal of the solvent under vacuum, the crude Boc-deprotected product was reacted with aldehyde 7 as described in Method B for the preparation of 101 (except using NaBH ₄ as the hydride source). After column purification (CH ₂ Cl ₂ / MeOH / NH ₄ OH 25: 1: 0.05 to 20: 1: 0.05 to 15: 1: 0.05) Isolated in% yield. ¹ H-NMR (300 MHz, CDCl ₃ / CD ₃ OD) δ 7.53-7.25 (m, 7H), 4.73 (m, 1H), 4.10 (t, J = 9 Hz, 1H), 3.79-3.57 (m, 3H), 3.49 (d, J = 5 Hz, 2H), 1.88 (s, 3H), 1.20 (d, J = 7 Hz, 3H). LCMS (ESI) m / e 429.2 (M + H) +.

アミド１０（０．１０１ｇ、０．５ｍｍｏｌ）をＣＨ_２Ｃｌ_２（２ｍＬ）中に０℃で溶解した。トリフルオロ酢酸（２ｍＬ）を加え、そして該混合物を０℃で３０分間撹拌し、その後に溶媒を真空下で除去した。該粗物に、メシレート３（０．１００ｇ、０．２３ｍｍｏｌ）、ＤＭＦ（３ｍＬ）およびヒューニッヒ塩基（０．３ｍＬ）を加え、そして該混合物を７５〜８０℃で２時間加熱した。該溶媒を真空下で除去し、そして該粗物を飽和ＮａＨＣＯ_３（３０ｍＬ）および１５％ＭｅＯＨ／ＣＨ_２Ｃｌ_２（３０ｍＬ）の間で分配した。該粗水相を１５％ＭｅＯＨ／ＣＨ_２Ｃｌ_２（２×３０ｍＬ）を用いて抽出し直し、該有機相を合わせて硫酸ナトリウム（Ｎａ_２ＳＯ_４）を用いて乾燥し、そして該溶媒を真空下で除去した。該粗物をシリカゲル（ＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨの２０：１：０．０５〜１５：１：０．０５）で精製して、白色吸湿性固体の化合物１０３（０．０３２ｇ、３２％）を得た。¹H-NMR (300 MHz, CDCl₃/CD₃OD) δ 7.70-7.28 (m, 7H), 4.82 (m, 1H), 4.15 (t, J = 9 Hz, 1H), 3.87-3.59 (m, 5H), 3.22 (m, 1H), 2.78 (s, 3H), 2.00 (s, 3H), 1.29 (d, J = 7 Hz, 3H)。LCMS (ESI) m/e 443.2 (M + H)⁺。 Example 4-Preparation of Compound 103

Amide 10 (0.101 g, 0.5 mmol) was dissolved in CH ₂ Cl ₂ (2 mL) at 0 ° C. Trifluoroacetic acid (2 mL) was added and the mixture was stirred at 0 ° C. for 30 minutes after which the solvent was removed in vacuo. To the crude was added mesylate 3 (0.100 g, 0.23 mmol), DMF (3 mL) and Hunig's base (0.3 mL), and the mixture was heated at 75-80 ° C. for 2 hours. The solvent was removed in vacuo and the crude was partitioned between saturated NaHCO ₃ (30 mL) and 15% MeOH / CH ₂ Cl ₂ (30 mL). The crude aqueous phase is re-extracted with 15% MeOH / CH ₂ Cl ₂ (2 × 30 mL), the organic phases are combined and dried using sodium sulfate (Na ₂ SO ₄ ), and the solvent is removed in vacuo. Removed below. The crude was purified on silica gel (CH ₂ Cl ₂ / MeOH / NH ₄ OH 20: 1: 0.05 to 15: 1: 0.05) to give white hygroscopic solid compound 103 (0.032 g, 32%). ¹ H-NMR (300 MHz, CDCl ₃ / CD ₃ OD) δ 7.70-7.28 (m, 7H), 4.82 (m, 1H), 4.15 (t, J = 9 Hz, 1H), 3.87-3.59 (m, 5H), 3.22 (m, 1H), 2.78 (s, 3H), 2.00 (s, 3H), 1.29 (d, J = 7 Hz, 3H). LCMS (ESI) m / e 443.2 (M + H) ⁺ .

化合物１０４は、化合物１０３について記載する通り（該粗物を溶媒の蒸留後に、直接にシリカゲルで精製（ＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨ（２０：１：０．０５〜１５：１：０．０５〜１２：１：０．０５）を用いて溶出）することを除く）、アミド１１およびメシレート３から製造して、白色固体の化合物１０４を得た。¹H-NMR (300 MHz, CDCl₃/CD₃OD) δ 7.51-7.21 (m, 7H), 4.72 (m, 1H), 4.08 (t, J = 9 Hz, 1H), 3.83-3.41 (m, 6H), 2.93 (m, 1H), 1.92 (s, 3H), 1.75 (d, J = 7 Hz, 3H)。LCMS (ESI) m/e 459.3 (M + H)⁺。 Example 5-Preparation of Compound 104

Compound 104 was prepared as described for compound 103 (the crude was purified directly on silica gel after distillation of the solvent (CH ₂ Cl ₂ / MeOH / NH ₄ OH (20: 1: 0.05 to 15: 1: 0 E.g., 5-12: 1: 0.05), and prepared from amide 11 and mesylate 3 to give compound 104 as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ / CD ₃ OD) δ 7.51-7.21 (m, 7H), 4.72 (m, 1H), 4.08 (t, J = 9 Hz, 1H), 3.83-3.41 (m, 6H), 2.93 (m, 1H), 1.92 (s, 3H), 1.75 (d, J = 7 Hz, 3H). LCMS (ESI) m / e 459.3 (M + H) ⁺ .

メチルアルコール（２ｍＬ）、塩化メチレン（２ｍＬ）およびヒューニッヒ塩基（２ｍＬ）の混合物中のアミン１２（これは、ヨード１および４−ホルミル−３−フルオロフェニルボロン酸から、実施例１のアミン５と同様な方法で製造する）の溶液に、ブロモアセトアミド６（３２ｍｇ、０．２３ｍｍｏｌ）を０℃で加えた。該反応混合物を室温まで昇温させ、そしてこのものを８０℃の油浴で１８時間加熱した。該溶液を濃縮し、そしてフラッシュクロマトグラフィー（１４：１：０．０５のＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨ）によって精製して、化合物１０５（６６ｍｇ）を得た。¹H-NMR (300 MHz, DMSO): δ 8.27 (t, J = 6 Hz, 1H), 7.65-7.54 (m, 3H), 7.44-7.35 (m, 4H), 7.14 (s, 1H), 4.81-4.72 (m, 1H), 4.17 (t, J = 9 Hz, 1H), 3.80-3.71 (m, 3H), 3.43 (t, J = 5 Hz, 2H), 3.13 (s, 2H), 1.84 (s, 3H)。LCMS (ESI) m/e 433 (M+H)⁺。 Example 6-Preparation of Compound 105

Amine 12 in a mixture of methyl alcohol (2 mL), methylene chloride (2 mL) and Hunig's base (2 mL), which is similar to amine 5 of Example 1 from iodo 1 and 4-formyl-3-fluorophenylboronic acid. Bromoacetamide 6 (32 mg, 0.23 mmol) was added at 0 ° C. The reaction mixture was allowed to warm to room temperature and heated in an 80 ° C. oil bath for 18 hours. The solution was concentrated and purified by flash chromatography (14: 1: 0.05 CH ₂ Cl ₂ / MeOH / NH ₄ OH) to give compound 105 (66 mg). ¹ H-NMR (300 MHz, DMSO): δ 8.27 (t, J = 6 Hz, 1H), 7.65-7.54 (m, 3H), 7.44-7.35 (m, 4H), 7.14 (s, 1H), 4.81 -4.72 (m, 1H), 4.17 (t, J = 9 Hz, 1H), 3.80-3.71 (m, 3H), 3.43 (t, J = 5 Hz, 2H), 3.13 (s, 2H), 1.84 ( s, 3H). LCMS (ESI) m / e 433 (M + H) ⁺ .

化合物１０６は、化合物１０３について記載する通りに、アミド１３およびメシレート３から製造した。該粗物を、シリカゲル（最初にＣＨ_２Ｃｌ_２／ＭｅＯＨ（２４：１〜２０：１）、次いでＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨ（２０：１：０．０５〜１５：１：０．０５）を用いて溶出）で精製して、白色吸湿性固体の化合物１０６を得た。¹H-NMR (300 MHz, CDCl₃) δ 7.47-7.21 (m, 7H), 5.98 (t, J = 6 Hz, 1H), 4.74 (m, 1H), 4.02 (t, J = 9 Hz, 1H), 3.78-3.48 (m, 6H), 2.93 (s, 3H), 2.91 (s, 3H), 1.97 (s, 3H), 1.17 (d, J = 7 Hz, 3H)。LCMS (ESI) m/e 457.3 (M + H)⁺。 Example 7-Preparation of Compound 106

Compound 106 was prepared from amide 13 and mesylate 3 as described for compound 103. The crude was purified on silica gel (first CH ₂ Cl ₂ / MeOH (24: 1 to 20: 1), then CH ₂ Cl ₂ / MeOH / NH ₄ OH (20: 1: 0.05 to 15: 1: 0). Elution) to give Compound 106 as a white hygroscopic solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.47-7.21 (m, 7H), 5.98 (t, J = 6 Hz, 1H), 4.74 (m, 1H), 4.02 (t, J = 9 Hz, 1H ), 3.78-3.48 (m, 6H), 2.93 (s, 3H), 2.91 (s, 3H), 1.97 (s, 3H), 1.17 (d, J = 7 Hz, 3H). LCMS (ESI) m / e 457.3 (M + H) ⁺ .

化合物１０７は、化合物１０３について記載する通り（反応液を１２時間加熱することを除く）、アミド１４およびメシレート３から製造した。該粗物をシリカゲル（ＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨの３０：１：０．０４〜２５：１：０．０４〜２０：１：０．０４〜１５：１：０．０５〜１５：１：０．１）で精製して、白色吸湿性固体の化合物１０７を得た。¹H-NMR (300 MHz, CDCl₃/CD₃OD) δ 7.48-7.20 (m, 7H), 4.74 (m, 1H), 4.07 (t, J = 9 Hz, 1H), 3.79-3.50 (m, 5H), 3.19 (m, 1H), 1.92 (s, 3H), 1.25 (d, J = 7 Hz, 3H)。LCMS (ESI) m/e 429.2 (M + H)⁺。 Example 8-Preparation of Compound 107

Compound 107 was prepared from amide 14 and mesylate 3 as described for compound 103 (except that the reaction was heated for 12 hours). The crude product on silica gel _{(CH 2 Cl 2 / MeOH /} NH 4 OH 30: 1: 0.04 to 25: 1: 0.04 to 20: 1: 0.04 to 15: 1: 0.05 to 15 : 0.1) to obtain a white hygroscopic solid compound 107. ¹ H-NMR (300 MHz, CDCl ₃ / CD ₃ OD) δ 7.48-7.20 (m, 7H), 4.74 (m, 1H), 4.07 (t, J = 9 Hz, 1H), 3.79-3.50 (m, 5H), 3.19 (m, 1H), 1.92 (s, 3H), 1.25 (d, J = 7 Hz, 3H). LCMS (ESI) m / e 429.2 (M + H) ⁺ .

ＭｅＯＨ（５ｍＬ）およびＣＨ_２Ｃｌ_２（５ｍＬ）中の２−ブロモアセトアミド６（８２７ｍｇ、５．８８ｍｍｏｌ）および４−ブロモベンジルエチルアミン１５（１．００ｇ、４．９０ｍｍｏｌ）の溶液に室温で、ヒューニッヒ塩基（１５ｍＬ）を加えた。該混合物を５０〜６０℃で１６時間撹拌した。水（３０ｍＬ）を加え、そして該混合物をＣＨ_２Ｃｌ_２（４×３０ｍＬ）を用いて抽出し、そしてＮａ_２ＳＯ_４を用いて乾燥して、白色結晶のアミド１６（１．２７ｇ、１００％収率）を得た。この生成物を更に精製することなく次の工程に使用した。¹H-NMR (300 MHz, CDCl₃, ppm): δ 7.38 (d, J = 8Hz, 2H), 7.09 (d, J = 8Hz, 1H), 6.77 (s br, 1H), 5.69 (s br, 1H), 3.67 (q, J = 7Hz, 1H), 3.07 (s, 2H), 1.29 (d, J = 7Hz, 3H)。 Example 9-Preparation of Compound 108

A solution of ₂ -bromoacetamide 6 (827 mg, 5.88 mmol) and 4-bromobenzylethylamine 15 (1.00 g, 4.90 mmol) in MeOH (5 mL) and CH ₂ Cl ₂ (5 mL) at room temperature at Hunig's base. (15 mL) was added. The mixture was stirred at 50-60 ° C. for 16 hours. Water (30 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (4 × 30 mL) and dried over Na ₂ SO ₄ to give white crystalline amide 16 (1.27 g, 100% Yield). This product was used in the next step without further purification. ¹ H-NMR (300 MHz, CDCl ₃ , ppm): δ 7.38 (d, J = 8Hz, 2H), 7.09 (d, J = 8Hz, 1H), 6.77 (s br, 1H), 5.69 (s br, 1H), 3.67 (q, J = 7Hz, 1H), 3.07 (s, 2H), 1.29 (d, J = 7Hz, 3H).

Boronic ester 17 (prepared as described in PCT International Patent Application WO 03 / 027083A1) (168 mg, 0.4 mmol) in dioxane (3 mL), EtOH (1 mL) and H ₂ O (1 mL). amide 16 (103 mg, 0.40 mmol), dichloro [1,1 ^'- bis (diphenylphosphino) ferrocene] palladium _{(II) (Pd (dppf)} 2 Cl 2, 16mg, 0.02mmol) and _K 2 _CO 3 ( 221 mg, 1.60 mmol). The mixture was degassed with argon and stirred at 90-95 ° C. for 3 hours. Water (10 mL) was added, the mixture was extracted with CH ₂ Cl ₂ (4 × 30 mL) and the extract was dried with Na ₂ SO ₄ . The residue was purified by column chromatography (7: 100: 0.1 MeOH / CH ₂ Cl ₂ / NH ₄ OH) to give compound 108 (85 mg, 50% yield). ¹ H-NMR (300 MHz, CDCl ₃ , ppm, partial): δ 7.70-7.30 (m, 7H), 7.09 (s br, 1H), 6.31 (s br, 1H), 5.63 (s br , 1H), 4.96-4.92 (m, 1H), 4.22 (t, J = 9Hz, 1H), 3.33 (s, 2H), 2.13 (s, 3H), 1.55 (d, J = 7Hz, 3H). LCMS (ESI) m / e 451.2 (M + Na) ⁺ .

ＤＭＦ（１０ｍＬ）中の高分子４−ヒドロキシ−２,３,５,６−テトラフルオロフェノールアミド樹脂（ＴＦＰ, J. Comb. Chem. 2000, 2, 691）（１．００ｇ、１．２７ｍｍｏｌ）の懸濁液を、ポリプロピレンカートリッジ（７０ｍＬ）中で１０分間振り混ぜ、次いでこのものをＮ−ｔｅｒｔ−ブトキシカルボニル−グリシン（１．１１ｇ、６．３５ｍｍｏｌ）、３−ヒドロキシベンゾトリアゾール（１８ｍｇ、０．１３ｍｍｏｌ）およびジイソプロピルカルボジイミド（１．２ｍＬ、７．６ｍｍｏｌ）を用いて処理した。該反応混合物を２３℃で１８時間振り混ぜ、次いで該樹脂をＤＭＦ（１０×５０ｍＬ）、ＴＨＦ（１０×５０ｍＬ）および塩化メチレン（１０×５０ｍＬ）を用いて洗浄し、そして真空下で乾燥した。 Example 10-Preparation of Compound 109

Of polymeric 4-hydroxy-2,3,5,6-tetrafluorophenolamide resin (TFP, J. Comb. Chem. 2000, 2, 691) (1.00 g, 1.27 mmol) in DMF (10 mL). The suspension was shaken in a polypropylene cartridge (70 mL) for 10 minutes, then this was N-tert-butoxycarbonyl-glycine (1.11 g, 6.35 mmol), 3-hydroxybenzotriazole (18 mg, 0.13 mmol). ) And diisopropylcarbodiimide (1.2 mL, 7.6 mmol). The reaction mixture was shaken at 23 ° C. for 18 hours, then the resin was washed with DMF (10 × 50 mL), THF (10 × 50 mL) and methylene chloride (10 × 50 mL) and dried under vacuum.

A suspension of TFP ester (270 mg, 0.216 mmol) in DMF (7 mL) is treated with amine 5 (70 mg, 0.196 mmol) and this is shaken in a polypropylene cartridge (10 mL) for 18 hours. It was. The filtrate was collected and dried to give amide 18 (90 mg, 0.175 mmol, 89%). ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.44-8.40 (m, 1H), 8.37-8.33 (m, 1H), 7.68-7.53 (m, 4H), 7.49-7.40 (m, 3H) , 7.12-7.08 (m, 1H), 4.87-4.79 (m, 1H), 4.39 (d, J = 6 Hz, 2H), 4.26-4.20 (m, 1H), 3.84 (dd, J = 9.6 Hz, 1H ), 3.66-3.62 (m, 2H), 3.52-3.48 (m, 2H), 1.91 (s, 3H), 1.46 (s, 9H).

A solution of amide 18 (90 mg, 0.175 mmol) in 4M HCl / dioxane (1 mL) was stirred at 23 ° C. for 0.5 h. The solvent was removed under vacuum. The reaction was diluted twice with dichloromethane (5 mL) and the solvent was evaporated under vacuum to give the hydrochloride salt of compound 109 (57 mg, 0.138 mmol, 79%). MS (ESI): 415.1 (M + H) ^<+> . ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 9.06-9.02 (m, 1H), 8.40-8.36 (m, 1H), 8.20 (s, 3H), 7.68-7.56 (m, 4H), 7.49 -7.45 (m, 3H), 4.87-4.78 (m, 1H), 4.46-4.44 (m, 2H), 4.26-4.20 (m, 1H), 3.85 (dd, J = 9.6 Hz, 1H), 3.72-3.65 (m, 2H), 3.51-3.47 (m, 2H), 1.90 (s, 3H).

ＣＨ_２Ｃｌ_２（２５ｍＬ）中のＢｏｃ−グリシン１９（１．０４ｇ、５．８８ｍｍｏｌ）および４−ブロモベンジルエチルアミン１５（１．００ｇ、４．９０ｍｍｏｌ）の溶液に室温で、ヒューニッヒ塩基（１．３０ｍＬ、７．３５ｍｍｏｌ）を加えた。該混合物を室温で１６時間撹拌した。該混合物を水（４０ｍＬ）および飽和ＮａＨＣＯ_３（３ｍＬ）中にそそぎ、次いでこのものをＣＨ_２Ｃｌ_２（６０ｍＬ）を用いて抽出し、水洗し（１００ｍＬ）、そしてＮａ_２ＳＯ_４を用いて乾燥した。該残渣をカラムクロマトグラフィー（ＥｔＯＡｃ／ヘキサン／ＮＨ_４ＯＨ（５０：５０：０．１））によって精製して、白色結晶のアミド２０（１．３０ｇ、６９％収率）を得た。¹H-NMR (300 MHz, CDCl₃, ppm): δ 7.37 (d, J = 7Hz, 2H), 7.09 (d, J = 7Hz, 1H), 6.50 (s br, 1H), 5.15 (s br, 1H), 5.01-4.95 (m, 1H), 3.69 (d, J = 6Hz, 2H), 1.39 (d, J = 7Hz, 3H), 1.37 (s, 9H)。 Example 11-Preparation of Compound 110

To a solution of Boc-glycine 19 (1.04 g, 5.88 mmol) and 4-bromobenzylethylamine 15 (1.00 g, 4.90 mmol) in CH ₂ Cl ₂ (25 mL) at room temperature, Hunig's base (1.30 mL). 7.35 mmol). The mixture was stirred at room temperature for 16 hours. The mixture is poured into water (40 mL) and saturated NaHCO ₃ (3 mL), which is then extracted with CH ₂ Cl ₂ (60 mL), washed with water (100 mL), and dried with Na ₂ SO _4. did. The residue was purified by column chromatography (EtOAc / hexane / NH ₄ OH (50: 50: 0.1)) to give white crystalline amide 20 (1.30 g, 69% yield). ¹ H-NMR (300 MHz, CDCl ₃ , ppm): δ 7.37 (d, J = 7Hz, 2H), 7.09 (d, J = 7Hz, 1H), 6.50 (s br, 1H), 5.15 (s br, 1H), 5.01-4.95 (m, 1H), 3.69 (d, J = 6Hz, 2H), 1.39 (d, J = 7Hz, 3H), 1.37 (s, 9H).

20 (143 mg, 0.40 mmol), boronate ester 17 (168 mg, 0.4 mmol), Pd (dppf) ₂ Cl ₂ (16 mg, in dioxane (3 mL), EtOH (1 mL), and H ₂ O (1 mL). 0.02 mmol) and K ₂ CO ₃ (221 mg, 1.60 mmol) were degassed with argon. The mixture was stirred at 90-95 ° C. for 3 hours. Water (10 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (4 × 30 mL) and the organic extract was dried with Na ₂ SO ₄ . The residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ / NH ₄ OH 5: 100: 0.1) to give the Boc-protected product (200 mg, 100% yield). To this intermediate was added CH ₂ Cl ₂ (2 mL) and TFA (2 mL) and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (MeOH / CH ₂ Cl ₂ / NH ₄ OH 15: 85: 0.1) to give compound 110 (168 mg, 99% yield). ) ¹ H-NMR (300 MHz, CDCl ₃ , ppm, partial): δ 7.64-7.33 (m, 7H), 5.13-5.07 (m, 1H), 4.19 (ddd, J = 9.3, 3Hz, 1H), 3.87 (ddd, J = 9.7, 3Hz, 1H), 3.77-3.50 (m, 5H), 1.99 (s, 3H), 1.54 (d, J = 7Hz, 3H). LCMS (ESI) m / e 429 (M + H) ⁺ .

Example 12 Preparation of Compound 11 A solution of amine 5 (70 mg, 0.20 mmol) in DMF (1 mL) was treated with diisopropylethylamine (0.068 mL, 0.39 mmol) and then cooled to 0 ° C. The reaction mixture was treated with N, N-dimethylglycine (20 mg, 0.20 mmol) and 1- (3-order methylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 41 mg, 0.22 mmol). . The reaction was stirred at 0 ° C. for 2 hours. Additional N, N-dimethylglycine (20 mg, 0.20 mmol) and EDCI (34 mg, 0.20 equiv) were added and the reaction was stirred at 23 ° C. for 24 hours. 3-Hydroxybenzotriazole (29 mg, 0.22 mmol) was added and the reaction was stirred at 23 ° C. for 16 hours. The reaction was diluted with toluene and the solvent removed in vacuo. The crude product was purified by preparative thin layer chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH 10: 1: 0.1) to give compound 111 (7 mg, 8% yield). MS (ESI): 443.1 (M + H) ^<+> . ¹ H-NMR (300 MHz, CH ₂ Cl ₂ ): δ 7.56-4.47 (m, 4H), 7.43-7.33 (m, 3H), 7.24-7.23 (m, 1H), 6.35-6.45 (m, 1H) , 4.84-4.76 (m, 1H), 4.52-4.50 (m, 2H), 4.10-4.04 (m, 1H), 3.81 (dd, J = 9.7 Hz, 1H), 3.71-3.61 (m, 2H), 3.02 (s, 2H), 2.29 (s, 6H), 2.02 (s, 3H).

Example 13-Preparation of Compound 113 Polymeric 4-hydroxy-2,3,5,6-tetrafluorophenol (TFP, J. Comb. Chem. 2000, 2, 691), amide resin in DMF (10 mL) (1.00 g, 1.27 mmol) suspension was shaken in a polypropylene cartridge (70 mL) for 10 minutes and then this was added to N-tert-butoxycarbonyl-glycine (1.11 g, 6.35 mmol), 3 -Treated with hydroxybenzotriazole (18 mg, 0.13 mmol) and diisopropylcarbodiimide (1.2 mL, 7.6 mmol). The reaction mixture was shaken at 23 ° C. for 18 hours, then the resin was washed with DMF (10 × 50 mL), THF (10 × 50 mL), and methylene chloride (10 × 50 mL) and dried under vacuum .

A suspension of TFP ester resin (0.051 g, 0.041 mmol) loaded with N-Boc glycine in DMF (1 mL) was treated with amine 12 (0.014 g, 0.037 mmol) and a polypropylene cartridge. (7 mL) and shaken for 12 hours. The filtrate was collected and evaporated to give the crude Boc-protected product (17 mg), which was dissolved in dichloromethane (2 mL) and ethanol (2 mL) and 4.0 M HCl / dioxane (5 mL) was added. Processed. The reaction was stirred at 23 ° C. for 2 hours. The solvent was removed under vacuum to give hydrochloride compound 113 (0.015 g, 0.032 mmol, 87% over 2 steps). MS (ESI): 433 (M + H) ^<+> .

ＤＭＦ（２ｍＬ）中のアミン２１（０．０７９ｇ、０．２１ｍｍｏｌ）の溶液を、Ｎ−Ｂｏｃ−グリシン（０．０５４ｇ、０．３１ｍｍｏｌ）およびＥＤＣＩ（０．０６０ｇ、０．３１ｍｍｏｌ）を用いて処理し、そして２３℃で２時間撹拌した。該反応混合物をジクロロメタン（５０ｍＬ）を用いて希釈し、１Ｍ塩酸（２×５０ｍＬ）および飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）を用いて洗浄し、そしてＮａ_２ＳＯ_４を用いて乾燥した。該溶媒を真空下で除去して、白色粉末のＢｏｃ−保護生成物（８９ｍｇ）を得た。ジクロロメタン（１５ｍＬ）およびメタノール（５ｍＬ）中の粗Ｂｏｃ−保護生成物の溶液を、ジオキサン（５ｍＬ）中の４．０Ｍ ＨＣｌ（５ｍＬ）を用いて処理し、そして２３℃で２時間撹拌した。該溶媒を真空下で除去することにより、塩酸塩の化合物１１４（０．０６５ｇ、６６％収率）を得た。MS (ESI): 433 (M + H)⁺。 Example 14-Preparation of Compound 114

Treatment of a solution of amine 21 (0.079 g, 0.21 mmol) in DMF (2 mL) with N-Boc-glycine (0.054 g, 0.31 mmol) and EDCI (0.060 g, 0.31 mmol). And stirred at 23 ° C. for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with 1M hydrochloric acid (2 × 50 mL) and saturated aqueous NaHCO ₃ (50 mL), and dried over Na ₂ SO ₄ . The solvent was removed under vacuum to give a Boc-protected product (89 mg) as a white powder. A solution of the crude Boc-protected product in dichloromethane (15 mL) and methanol (5 mL) was treated with 4.0 M HCl (5 mL) in dioxane (5 mL) and stirred at 23 ° C. for 2 hours. The solvent was removed under vacuum to give the hydrochloride compound 114 (0.065 g, 66% yield). MS (ESI): 433 (M + H) ^<+> .

ＤＭＦ（１．０ｍＬ）中のアミン５（０．０７０ｇ、０．２０ｍｍｏｌ）の懸濁液をジイソプロピルエチルアミン（０．０６８ｍＬ、０．４０ｍｍｏｌ）を用いて処理し、そして溶解が達成するまで加熱した。該反応混合物を０℃まで冷却し、そしてＮ−ｔｅｒｔ−ブトキシカルボニル−アラニン（０．０３７ｇ、０．２０ｍｍｏｌ）およびＥＤＣＩ（０．０４１ｇ、０．２２ｍｍｏｌ）を用いて処理した。更なるＮ−ｔｅｒｔ−ブトキシカルボニル−アラニン（０．０３７ｇ、０．２０ｍｍｏｌ）およびＥＤＣＩ（０．０３４ｇ、０．１８ｍｍｏｌ）を加え、そして該反応混合物を２３℃で１２時間撹拌した。１−ヒドロキシベンゾトリアゾール（０．０２９ｇ、０．２２ｍｍｏｌ）を加えた。該反応混合物をトルエン中に希釈し、そして該溶媒を真空下で除去して粗生成物を得て、このものをフラッシュクロマトグラフィー（ＥｔＯＡｃ／ＣＨ_２Ｃｌ_２（１：１）中の２〜５％ＭｅＯＨ）によって精製して、アミド２２（０．０５３ｇ、５０％収率）を得た。 Example 15-Preparation of Compound 117

A suspension of amine 5 (0.070 g, 0.20 mmol) in DMF (1.0 mL) was treated with diisopropylethylamine (0.068 mL, 0.40 mmol) and heated until dissolution was achieved. The reaction mixture was cooled to 0 ° C. and treated with N-tert-butoxycarbonyl-alanine (0.037 g, 0.20 mmol) and EDCI (0.041 g, 0.22 mmol). Additional N-tert-butoxycarbonyl-alanine (0.037 g, 0.20 mmol) and EDCI (0.034 g, 0.18 mmol) were added and the reaction mixture was stirred at 23 ° C. for 12 hours. 1-Hydroxybenzotriazole (0.029 g, 0.22 mmol) was added. The reaction mixture is diluted in toluene and the solvent is removed in vacuo to give the crude product which is purified by flash chromatography (2-5 in EtOAc / CH ₂ Cl ₂ (1: 1). % MeOH) to give amide 22 (0.053 g, 50% yield).

A solution of amide 22 (0.042 g, 0.080 mmol) in methylene chloride (1.0 mL) was treated with hydrogen chloride (4.0 M in dioxane, 0.24 mL) and at 23 ° C. for 1 hour. Stir. The reaction mixture was diluted with methylene chloride and the solvent was removed in vacuo to give compound 17. MS (ESI): 429 (M + H) ^<+> .

ＤＭＦ（０．５６ｍＬ）中のアミン５（０．０２０ｇ、０．０５６ｍｍｏｌ）の溶液を、Ｎ−ｔｅｒｔ−ブトキシカルボニル−Ｄ−アラニン（０．０１２ｇ、０．０６２ｍｍｏｌ）およびＥＤＣＩ（０．０１６ｇ、０．０８４ｍｍｏｌ）を用いて処理し、そして２３℃で１．５時間撹拌した。該反応混合物を塩化メチレン（１５ｍＬ）を用いて希釈し、１．０Ｍ塩酸（２×１５ｍＬ）および飽和炭酸水素ナトリウム水溶液（１５ｍＬ）を用いて洗浄し、そしてＮａ_２ＳＯ_４を用いて乾燥して、アミド２３を得た。 Example 16-Preparation of Compound 119

A solution of amine 5 (0.020 g, 0.056 mmol) in DMF (0.56 mL) was added to N-tert-butoxycarbonyl-D-alanine (0.012 g, 0.062 mmol) and EDCI (0.016 g, 0 0.084 mmol) and stirred at 23 ° C. for 1.5 hours. The reaction mixture is diluted with methylene chloride (15 mL), washed with 1.0 M hydrochloric acid (2 × 15 mL) and saturated aqueous sodium bicarbonate (15 mL), and dried over Na ₂ SO _4. Amide 23 was obtained.

A solution of amide 23 (0.045 g, 0.085 mmol) in methylene chloride (1.0 ml) was treated with hydrogen chloride (4.0 M in dioxane, 0.50 mL) and at 23 ° C. for 1 hour. Stir. The reaction mixture was diluted with methylene chloride and the solvent was removed in vacuo to give compound 119. MS (ESI): 429 (M + H) ^<+> .

ＤＭＦ（０．５０ｍＬ）中のアミン５（０．０５０ｇ、０．１４ｍｍｏｌ）溶液を、Ｎ−ｔｅｒｔ−ブトキシカルボニル−Ｄ−セリン（０．０３２ｇ、０．１５ｍｍｏｌ）、４−ジメチルアミノピリジン（ＤＭＡＰ、ＤＭＦ中の０．８Ｍ、０．１７ｍＬ、０．１４ｍｍｏｌ）およびＥＤＣＩ（０．０３０ｇ、０．１５ｍｍｏｌ）を用いて処理し、そして２３℃で０．５時間撹拌した。該反応混合物をシリカゲルカラムに直接に加え、そしてフラッシュクロマトグラフィー（５０〜１００％アセトン／ヘキサン）によって精製して、アミド２４（０．０３８ｇ、４８％収率）を得た。 Example 17-Preparation of Compound 126

A solution of amine 5 (0.050 g, 0.14 mmol) in DMF (0.50 mL) was added to N-tert-butoxycarbonyl-D-serine (0.032 g, 0.15 mmol), 4-dimethylaminopyridine (DMAP, Treated with 0.8M in DMF, 0.17 mL, 0.14 mmol) and EDCI (0.030 g, 0.15 mmol) and stirred at 23 ° C. for 0.5 h. The reaction mixture was added directly to a silica gel column and purified by flash chromatography (50-100% acetone / hexanes) to give amide 24 (0.038 g, 48% yield).

A solution of amide 24 (0.038 g, 0.067 mmol) in methylene chloride (1.0 mL) was treated with hydrogen chloride (4.0 M in dioxane, 0.80 mL) and at 23 ° C. for 1 hour. Stir. The reaction mixture was diluted with methylene chloride and the solvent was removed in vacuo to give compound 126. MS (ESI): 445 (M + H) ^<+> .

Example 18 Preparation of Compound 127 A solution of amine 5 (0.025 g, 0.07 mmol) in DMF (0.5 mL) was added to N-Boc-glutamic acid (0.054 g, 0.08 mmol), DMAP (0.010 g). , 0.08 mmol) and EDCI (0.016 g, 0.08 mmol) and stirred at 23 ° C. for 2 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with 1M HCl (2 × 10 mL) and saturated aqueous NaHCO ₃ (10 mL), and dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give the Boc-protected product (62 mg) as a white solid, which was further purified by silica gel chromatography (acetone) to give the Boc-protected amine (41 mg) as a white powder. Obtained. This solid was dissolved in THF (0.5 mL), cooled to 0 ° C., and treated with 2N HCl in dioxane (0.1 mL). The mixture was stirred at 0 ° C. for 4 hours and then concentrated to give hygroscopic white solid compound 127 hydrochloride (0.029 g, 0.06 mL, 86% over 2 steps). MS (ESI): 486 (M + H) ⁺ .

Example 19 Preparation of Compound 129 A solution of amine 5 (0.025 g, 0.07 mmol) in DMF (0.5 mL) was added to N-Boc-L-methionine (0.020 g, 0.08 mmol), DMAP (0 .010 g, 0.08 mmol) and EDCI (0.016 g, 0.08 mmol) and this was stirred at 23 ° C. for 2 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with 1M HCl (2 × 10 mL) and saturated aqueous NaHCO ₃ (10 mL), and dried over Na ₂ SO ₄ . The solvent was removed under vacuum to give the Boc-protected product (62 mg) as a white solid, which was further purified by silica gel chromatography (acetone) to give pure Boc-protected amine ( 34 mg) was obtained. This solid was dissolved in THF (0.5 mL), cooled to 0 ° C. and treated with 2M HCl in dioxane (0.1 mL). The mixture was stirred at 0 ° C. for 4 hours, then concentrated to give the hydrochloride salt of Compound 129 (0.027 g, 0.055 mmol, 79% over 2 steps) as a hygroscopic white solid. MS (ESI): 489 (M + H) ^<+> .

Example 20 Preparation of Compound 138 To a solution of compound 129 (0.010 g, 0.02 mmol) in dichloromethane (0.5 mL) and methanol (0.5 mL) at 0 ° C. was added 3-chloroperoxybenzoic acid (0. 005 g, 0.03 mmol) was added and the solution was stirred at 0 ° C. for 6 hours. The solution was diluted with dichloromethane (30 mL) and washed with saturated aqueous NaHCO ₃ and brine. The crude product was purified by silica gel chromatography (acetone) to give white solid compound 138 (0.011 g, 0.02 mmol, 100% yield). MS (ESI): 521 (M + H) ⁺ .

無水ＣＨ_２Ｃｌ_２（１０ｍＬ）、ＭｅＯＨ（１０ｍＬ）およびヒューニッヒ塩基（４ｍＬ）中のグリシンアミド塩酸塩８（０．４０ｇ、３．４０ｍｍｏｌ）およびメシル−オキサゾリジノン２５（０．５０ｇ、１．１０ｍｍｏｌ）の混合物を、８０℃〜８５℃の間で６０時間加熱した。該溶媒を真空下で除去し、そして該粗物を希水酸化アンモニウム（ｐＨ＝１０）中で懸濁し、そしてろ過した。該残渣を乾燥し、そしてシリカゲルクロマトグラフィー（１％ ＭｅＯＨ／ＣＨ_２Ｃｌ_２、次いで１６：１：０．１〜１２：１：０．１のＣＨ_２Ｃｌ_２／ＭｅＯＨ／ＮＨ_４ＯＨ）によって精製して、白色固体の化合物１４６（０．１９２ｇ、４１％）を得た。LCMS (ESI): m/e 429.1 (M + H)⁺。 Example 21-Preparation of Compound 146

Anhydrous _{CH 2 Cl 2 (10mL),} MeOH (10mL) and Hunig's base (4 mL) glycinamide hydrochloride in 8 (0.40g, 3.40mmol) and mesyl - oxazolidinone 25 (0.50 g, 1.10 mmol) The mixture was heated between 80 ° C. and 85 ° C. for 60 hours. The solvent was removed in vacuo and the crude was suspended in dilute ammonium hydroxide (pH = 10) and filtered. The residue was dried and purified by silica gel chromatography (1% MeOH / CH ₂ Cl ₂ then 16: 1: 0.1 to 12: 1: 0.1 CH ₂ Cl ₂ / MeOH / NH ₄ OH). Thus, a white solid compound 146 (0.192 g, 41%) was obtained. LCMS (ESI): m / e 429.1 (M + H) ⁺ .

ＤＭＦ（０．５０ｍＬ）中のアミン２６（０．０５０ｇ、０．１４ｍｍｏｌ）の溶液を、Ｎ−ｔｅｒｔ−ブトキシカルボニル−グリシン（０．０２６ｇ、０．１５ｍｍｏｌ）、ＤＭＡＰ（ＤＭＦ中の０．８Ｍ、０．１７ｍＬ、０．１４ｍｍｏｌ）、およびＥＤＣＩ（０．０３０ｇ、０．１５ｍｍｏｌ）を用いて処理し、そして２３℃で０．５時間撹拌した。該反応混合物をシリカゲルカラムに直接に加え、そしてこのものをフラッシュクロマトグラフィー（５０〜１００％アセトン／ヘキサン）によって精製して、アミド２７（０．０３１ｇ、４２％収率）を得た。 Example 22-Preparation of Compound 148

A solution of amine 26 (0.050 g, 0.14 mmol) in DMF (0.50 mL) was added to N-tert-butoxycarbonyl-glycine (0.026 g, 0.15 mmol), DMAP (0.8 M in DMF, 0.17 mL, 0.14 mmol), and EDCI (0.030 g, 0.15 mmol) and stirred at 23 ° C. for 0.5 h. The reaction mixture was added directly to a silica gel column and this was purified by flash chromatography (50-100% acetone / hexanes) to give amide 27 (0.031 g, 42% yield).

A solution of amide 27 (0.093 g, 0.18 mmol) was treated with hydrogen chloride (4.0 M in dioxane, 1.0 mL) and stirred at 23 ° C. for 0.5 h. The reaction mixture was diluted with methylene chloride and the solvent was removed in vacuo to give compound 148 (0.082 g, 100% yield). MS (ESI): 429 (M + H) ^<+> .

Example 23-Preparation of Compound 150 A solution of amine 5 (0.18 g, 0.50 mmol) in DMF (2 mL) was added to acetoxyacetic acid (0.065 g, 0.55 mmol), EDCI (0.11 g, 0.55 mmol). ) And DMAP (0.061 g, 0.50 mmol) and stirred at 23 ° C. for 2 hours. The reaction mixture was purified by flash chromatography (50-100% acetone / hexanes) to give the O-acetylated product (120 mg, 0.26 mmol, 52%). A solution of the O-acetylated product (0.11 g, 0.24 mmol) in THF / methanol / H ₂ O (3: 1: 1) (2.5 mL) was added to lithium hydroxide monohydrate (0. 0. 020 g, 0.48 mmol) and stirred at 23 ° C. for 15 minutes. The reaction mixture was diluted with dichloromethane (50 mL), washed with 1M hydrochloric acid (50 mL) and dried with Na ₂ SO ₄ . The solvent was removed in vacuo to give white powder of compound 150 (90 mg, 90% yield). MS (ESI): 416 (M + H) ^<+> .

Example 24 Preparation of Compound 157 A solution of mesylate 3 (220 mg, 0.5 mmol, 1 eq) in DMF (2 mL) and THF (2 mL) was added to a Hunig base (0.3 mL, 1.0 mmol, 2 eq) and Treated with thiosemicarbazide (180 mg, 2.0 mmol, 4.0 equiv) at room temperature, the resulting mixture was heated to reflux and stirred for 6 hours. The desired product that precipitated from the reaction mixture was collected by filtration. Purification by column chromatography (eluting with a 5-10% MeOH / CH ₂ Cl ₂ gradient) gave (5S) -N- [3- ( ^4′ -N-thiocarbamoylhydrazinomethyl) as an off-white solid. -2-Fluoro-biphenyl-4-yl) -2-oxo-oxazolidine-5-ylmethyl] -acetamide 157 (52 mg, theoretical yield 215.5 mg, 24%) was obtained. Calculated as _{C 20 H 22 FN 5 O 3} S, LCMS (EI): m / e 432 (M + + H).

ジオキサン（２０ｍＬ）およびピリジン（４ｍＬ）中のＢｏｃ−Ｓｅｒ−ＯＨ ２８（２．０ｇ、８．０２２ｍｍｏｌ）溶液に、二炭酸ジ−ｔｅｒｔ−ブチル（２．１ｇ、９．６２６ｍｍｏｌ）を加えた。該混合物を室温で１０分間撹拌し、次いで炭酸水素アンモニウム（３．１７ｇ、４０．１１ｍｍｏｌ）を加え、そして該反応混合物を室温で１６時間撹拌した。得られた混合物を酢酸エチル（５０ｍＬ）を用いて希釈し、そして飽和炭酸ナトリウム水溶液（５０ｍＬ）および飽和塩化ナトリウム（５０ｍＬ）を用いて洗浄し、Ｎａ_２ＳＯ_４を用いて乾燥し、そして真空下で蒸発した。該残渣をＴＦＡ（５ｍＬ）中に溶解し、そして室温で３０分間撹拌した。該混合物を真空下で濃縮し、そして酢酸エチル（１００ｍＬ）および炭酸ナトリウム水溶液（１００ｍＬ）の間で分配した。該混合物を激しく振り混ぜ、そして相分離した。該有機相をブライン（１００ｍＬ）を用いて洗浄し、無水Ｎａ_２ＳＯ_４を用いて乾燥し、そして真空下で濃縮して、無色油状物のアミド２９（０．８５ｇ）を得た。この物質を更に精製することなく次の反応に用いた。 Example 25-Preparation of Compound 170

To a solution of Boc-Ser-OH 28 (2.0 g, 8.022 mmol) in dioxane (20 mL) and pyridine (4 mL) was added di-tert-butyl dicarbonate (2.1 g, 9.626 mmol). The mixture was stirred at room temperature for 10 minutes, then ammonium bicarbonate (3.17 g, 40.11 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture is diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium carbonate (50 mL) and saturated sodium chloride (50 mL), dried with Na ₂ SO ₄ and under vacuum. Evaporated. The residue was dissolved in TFA (5 mL) and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and partitioned between ethyl acetate (100 mL) and aqueous sodium carbonate (100 mL). The mixture was shaken vigorously and the phases separated. The organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give amide 29 (0.85 g) as a colorless oil. This material was used in the next reaction without further purification.

A mixture of mesylate 3 (0.1 g, 0.229 mmol) and amide 29 (0.02 g, 0.229 mmol) in dimethyl sulfoxide (5 mL) and K ₂ CO ₃ (0.06 g, 0.458 mmol) at 80 ° C. Heated for 16 hours. The reaction was cooled, diluted with ethyl acetate and washed with water (50 mL) and brine (50 mL). Drying with Na ₂ SO ₄ and concentrating in vacuo gave a yellow solid that was purified by preparative thin layer chromatography (95% CH ₂ Cl ₂ , 5% MeOH), Compound 170 as a white solid was obtained. LCMS (ESI): 445 (M + H) ^<+> . ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 8.25 (t, J = 5 Hz, 1H), 7.61-7.39 (m, 7H), 5.25 (s, 1H), 4.75 (m, 1H), 4.54 (s, 2H), 4.15 (t, J = 9 Hz, 1H), 3.77 (m, 1H), 3.43 (d, 2H), 1.8 (s, 3H).

Example 26-Preparation of Compound 173 Compound 101 (0.25 g, 0.61 mmol), acetoacetic acid 5 (0.09 g, 0.73 mmol) and 1-hydroxybenzotriazole (0.10 g, 0.73 mmol) were combined with DMF ( 8 mL) and to this solution was added EDCI (0.14 g, 0.73 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue was partitioned between 20% MeOH / CH ₂ Cl ₂ (40 mL) and water (40 mL). The two phases were separated, the aqueous phase was extracted with 20% MeOH / CH ₂ Cl ₂ (3 × 30 mL), and the organic phases were combined and dried using Na ₂ SO ₄ . The solvent was removed in vacuo and the crude was purified by silica gel chromatography (1-10% MeOH / CH ₂ Cl ₂ ) to give a yellow-white solid compound 173 (0.116 g, 37%). Got. LCMS (ESI): m / e 537.1 (M + Na) ⁺ .

  The complete disclosure of each of the patent and scientific documents cited herein forms part of the present specification.

  The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the above embodiments are to be considered in all respects illustrative rather than limiting on the invention described herein. The scope of the invention is, therefore, indicated by the claims rather than by the foregoing description, and all modifications that come within the meaning and range of equivalency of the claims are intended to be embraced herein. .

Claims (45)

formula:

Or a pharmaceutically acceptable salt, ester or prodrug thereof.
[Where:
A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
Het-CH ₂ -R ³ has the formula:

Selected from the group consisting of:
M is the formula:

(Where
L ¹ is a bond, or C _1-6 alkyl, optionally substituted with one or more R ⁴ groups;
L ² is a bond, or C _1-6 alkyl, optionally substituted with one or more R ⁴ groups;
Q is selected from the group consisting of a) H, b) —NR ⁴ R ⁴ , c) —OR ⁴ , and d) C _1-6 alkyl optionally substituted with one or more R ⁴ groups; ,
W is selected from the group consisting of O and S)
Having
X ^{is, a) -NR 4 -, b} ) -NR 4 NR 4 -, and c) is selected from the group consisting of -S-;
L is C _1-6 alkyl optionally substituted with one or more R ⁴ groups;
Each R ¹ is independently
_{a) F, b) Cl,} c) Br, d) I, e) -CF 3, f) -OR 7, g) -CN, h) -NO 2, i) -NR 7 R 7, j) - ^{C (O) R 7, k} ) -C (O) OR 7, l) -OC (O) R 7, m) -C (O) NR 7 R 7, n) -NR 7 C (O) R 7 ^{, o) -OC (O) NR} 7 R 7, p) -NR 7 C (O) OR 7, q) -NR 7 C (O) NR 7 R 7, r) -C (S) R 7, s ^{) -C (S) OR 7,} t) -OC (S) R 7, u) -C (S) NR 7 R 7, v) -NR 7 C (S) R 7, w) -OC (S) ^{NR 7 R 7, x) -NR} 7 C (S) OR 7, y) -NR 7 C (S) NR 7 R 7, z) -C (NR 7) R 7, aa) -C (NR 7) ^{OR 7, bb) -OC (NR} 7) R 7, cc) -C (NR 7) NR 7 R 7, dd) -NR 7 C (NR 7) R 7, e ^{) -OC (NR 7) NR 7} R 7, ff) -NR 7 C (NR 7) OR 7, gg) -NR 7 C (NR 7) NR 7 R 7, hh) -S (O) p R 7 _{^{, ii) -SO 2 NR 7 R}} 7, and jj) ^{R 7}
Selected from the group consisting of:
Each R ² is independently
_{a) F, b) Cl,} c) Br, d) I, e) -CF 3, f) -OR 7, g) -CN, h) -NO 2, i) -NR 7 R 7, j) - ^{C (O) R 7, k} ) -C (O) OR 7, l) -OC (O) R 7, m) -C (O) NR 7 R 7, n) -NR 7 C (O) R 7 ^{, o) -OC (O) NR} 7 R 7, p) -NR 7 C (O) OR 7, q) -NR 7 C (O) NR 7 R 7, r) -C (S) R 7, s ^{) -C (S) OR 7,} t) -OC (S) R 7, u) -C (S) NR 7 R 7, v) -NR 7 C (S) R 7, w) -OC (S) ^{NR 7 R 7, x) -NR} 7 C (S) OR 7, y) -NR 7 C (S) NR 7 R 7, z) -C (NR 7) R 7, aa) -C (NR 7) ^{OR 7, bb) -OC (NR} 7) R 7, cc) -C (NR 7) NR 7 R 7, dd) -NR 7 C (NR 7) R 7, e ^{) -OC (NR 7) NR 7} R 7, ff) -NR 7 C (NR 7) OR 7, gg) -NR 7 C (NR 7) NR 7 R 7, hh) -S (O) p R 7 _{^{, ii) -SO 2 NR 7 R}} 7, and jj) ^{R 7}
Selected from the group consisting of:
R ³ is
^{a) -OR 7, b) -NR} 7 R 7, c) -C (O) R 7, d) -C (O) OR 7, e) -OC (O) R 7, f) -C (O ^{) NR 7 R 7, g)} -NR 7 C (O) R 7, h) -OC (O) NR 7 R 7, i) -NR 7 C (O) OR 7, j) -NR 7 C (O ^{) NR 7 R 7, k)} -C (S) R 7, l) -C (S) OR 7, m) -OC (S) R 7, n) -C (S) NR 7 R 7, o) ^{-NR 7 C (S) R 7} , p) -OC (S) NR 7 R 7, q) -NR 7 C (S) OR 7, r) -NR 7 C (S) NR 7 R 7, s) ^{-C (NR 7) R 7,} t) -C (NR 7) OR 7, u) -OC (NR 7) R 7, v) -C (NR 7) NR 7 R 7, w) -NR 7 C ^{(NR 7) R 7, x} ) -OC (NR 7) NR 7 R 7, y) -NR 7 C (NR 7) OR 7, z) -NR 7 C (NR 7 ^{) NR 7 R 7, aa)} -S (O) p R 7, bb) -SO 2 NR 7 R 7 and cc) ^{R 7,}
Selected from the group consisting of:
Each R ⁴ is independently
^{a) H, b) = O} , c) = S, d) = NR 5, e) = NOR 5, f) = N-NR 5 R 5, g) -OR 5, h) -NO 2, i) ^{-NR 5 R 5, j) -C} (O) R 5, k) -C (O) OR 5, l) -OC (O) R 5, m) -C (O) NR 5 R 5, n) ^{-NR 5 C (O) R 5} , o) -OC (O) NR 5 R 5, p) -NR 5 C (O) OR 5, q) -NR 5 C (O) NR 5 R 5, r) ^{-C (S) R 5, s} ) -C (S) OR 5, t) -OC (S) R 5, u) -C (S) NR 5 R 5, v) -NR 5 C (S) R ^{5, w) -OC (S)} NR 5 R 5, x) -R 5 C (S) OR 5, y) -NR 5 C (S) NR 5 R 5, z) -C (NR 5) R 5 ^{, aa) -C (NR 5)} OR 5, bb) -OC (NR 5) R 5, cc) -C (NR 5) NR 5 R 5, dd) -NR 5 ^{(NR 5) R 5, ee} ) -OC (NR 5) NR 5 R 5, ff) -NR 5 C (NR 5) OR 5, gg) -NR 5 C (NR 5) NR 5 R 5, hh) -S (O) _p R ^5, and ii) ^{R 5}
Selected from the group consisting of:
Each R ⁵ is independently
a) H, b) C _1-6 alkyl, c) —C (O) —C _1-6 alkyl, and d) —C (O) O—C _1-6 alkyl, wherein , B) -d) are optionally substituted with one or more R ⁶ groups;
Each R ⁶ is independently
a) —OH, b) —OC _1-6 alkyl, c) —SH, d) —NO ₂ , e) —NH ₂ , f) —NHC _1-6 alkyl, g) —N (C _1-6 alkyl) ) ₂ , h) -C (O) H, i) -C (O) OH, j) -C (O) C _1-6 alkyl, k) -OC (O) C _1-6 alkyl, l)- C (O) OC _1-6 alkyl, m) -C (O) NH ₂ , n) -C (O) NHC _1-6 alkyl, o) -C (O) N (C _1-6 alkyl) ₂ , selected from the group consisting of p) -NHC (O) C _1-6 alkyl, and q) -S (O) _p C _1-6 alkyl;
Each R ⁷ is independently
a) H, b) C _1-6 alkyl, c) C _2-6 alkenyl, d) C _2-6 alkynyl, e) C _3-14 saturated, unsaturated or aromatic carbocyclic ring, f) nitrogen, saturation of oxygen and 3 to 14-membered containing one or more heteroatoms selected from the group consisting of sulfur, unsaturated or aromatic heterocyclic _{ring, g) -C (O) -C} 1~6 alkyl, h) - C (O) —C _2-6 alkenyl, i) —C (O) —C _2-6 alkynyl, j) —C (O) —C _3-14 saturated, unsaturated or aromatic carbocycle, k ) -C (O) -3 to 14-membered saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, l) -C (O) _{O-C 1 to 6 alkyl, m) -C (O) O} -C 2~6 _{alkenyl, n) -C (O) O} -C 2~6 alkynyl, o) - (O) saturated O-C _{3 to 14,} unsaturated or aromatic carbocycle, and p) a nitrogen, oxygen, and -C containing one or more heteroatoms selected from the group consisting of sulfur (O) Selected from the group consisting of O-3 to 14-membered saturated, unsaturated or aromatic heterocycles, wherein any of b) to p) is optionally substituted with one or more R ⁸ groups;
Each R ⁸ is independently
a) F, b) Cl, c) Br, d) I, e) = O, f) = S, g) = NR 9, h) = NOR 9, i) = N-NR 9 R 9, j) _{^{-CF 3, k) -OR 9,}} l) -CN, m) -NO 2, n) -NR 9 R 9, o) -C (O) R 9, p) -C (O) OR 9, q ^{) -OC (O) R 9,} r) - (O) NR 9 R 9, s) -NR 9 C (O) R 9, t) -OC (O) NR 9 R 9, u) -NR 9 C ^{(O) OR 9, v)} -NR 9 C (O) NR 9 R 9, w) -C (S) R 9, x) -C (S) OR 9, y) -OC (S) R 9, ^{z) -C (S) NR 9} R 9, aa) -NR 9 C (S) R 9, bb) -OC (S) NR 9 R 9, cc) -NR 9 C (S) OR 9, dd) ^{-NR 9 C (S) NR 9} R 9, ee) -C (NR 9) R 9, ff) -C (NR 9) OR 9, gg) -OC ^{(NR 9) R 9, hh} ) -C (NR 9) NR 9 R 9, ii) -NR 9 C (NR 9) R 9, jj) -OC (NR 9) NR 9 R 9, kk) -NR ⁹ C (NR ⁹ ) OR ⁹ , ll) -NR ⁹ C (NR ⁹ ) NR ⁹ R ⁹ , mm) -S (O) _p R ⁹ , nn) -SO ₂ NR ⁹ R ⁹ , and oo) R ⁹
Selected from the group consisting of
Each R ⁹ is independently
_{a) H, b) C} 1~6 alkyl, _{c) C 2 to 6} alkenyl, _{d) C 2 to 6} alkynyl, e) saturated C3～14, unsaturated or aromatic carbocycle, f) nitrogen, oxygen and saturated 3 to 14 membered containing one or more heteroatoms selected from the group consisting of sulfur, unsaturated or aromatic _{heterocycle, g) -C (O) -C} 1~6 alkyl, h) - C (O) —C _2-6 alkenyl, i) —C (O) —C _2-6 alkynyl, j) —C (O) —C _3-14 saturated, unsaturated or aromatic carbocycle, k ) -C (O) -3 to 14-membered saturated, unsaturated or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, l) -C (O) _{O-C 1 to 6 alkyl, m) -C (O) O} -C 2~6 alkenyl, n) -C (O) O -C2~6 alkynyl, o) - C (O) O—C 3-14 containing a saturated, unsaturated or aromatic carbocycle, and p) one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, —C (O) Selected from the group consisting of O-3-14 membered saturated, unsaturated or aromatic heterocycles, wherein any of b) -p) is optionally
a) F, b) Cl, c) Br, d) I, e) -CF 3, f) -OH, g) -OC 1~6 _{alkyl, h) -SH, i) -SC} 1~6 alkyl, _{j) -CN, k) -NO 2} , l) -NH 2, m) -NHC 1~6 _alkyl, n) -N _(C 1~6 _{alkyl) 2, o) -C (O} ) C 1~6 _{alkyl, p) -OC (O) C} 1~6 _{alkyl, q) -C (O) OC} 1~6 _{alkyl, r) -C (O) NH} 2, s) -C (O) NHC 1~6 alkyl , t) -C (O) N (C 1~6 _{alkyl) 2, u) -NHC (O} ) C 1~6 _{alkyl, v) -SO 2 NH 2 -} , w) -SO 2 NHC 1~6 alkyl , x) is substituted with -SO ₂ N _{(C 1 to 6 alkyl) 2,} and y) -S (O) 1 or more moieties selected from the group consisting of _p C _{1 to 6} alkyl;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4; and
Each p is independently 0, 1, or 2;
However, the compound has the formula:

Does not have a formula selected from the group consisting of] formula:

[Wherein A, B, L, M, R ¹ , R ² , R ³ , X, m, and n are defined as described in claim 1]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein A, B, L, M, R ¹ , R ² , R ³ , X, m and n are defined as defined in claim 1]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. A is selected from the group consisting of phenyl and pyridyl;
B is selected from the group consisting of phenyl and pyridyl;
m is 0, 1, or 2; and
n is 0, 1, or 2.
The compound according to any one of claims 1 to 3. AB is the formula:

Wherein A, R ² and n are defined as described in claim 1
The compound according to any one of claims 1 to 4, wherein AB is the formula:

[Wherein A is defined as described in claim 1]
The compound according to claim 5, wherein AB is the formula:

[Wherein A is defined as described in claim 1]
The compound according to claim 5, wherein AB is the formula:

[Wherein B is defined as defined in claim 1]
The compound according to any one of claims 1 to 7, wherein AB is the formula:

[Wherein B is defined as defined in claim 1]
The compound according to any one of claims 1 to 7, wherein R ³ is -NHC (O) ^{R 7,} The compound according to any one of claims 1 to 9. R ³ is -NHC (O) CH _3, wherein compound of claim 10. R ³ is the formula:

The compound according to any one of claims 1 to 9, wherein formula:

[Wherein A, B, L, M, R ¹ , R ² , X, m, and n are defined as described in claim 1]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein A, L, M, R ¹ , R ³ , X, and m are defined as described in claim 1]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein A, L, M, R ¹ , X and m are defined as described in claim 1]
15. A compound according to claim 14 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M, R ³ and X are defined as described in claim 1]
15. A compound according to claim 14 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M and X are defined as defined in claim 1]
17. A compound according to claim 16 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M, R ³ and X are defined as described in claim 1]
15. A compound according to claim 14 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M and X are defined as defined in claim 1]
19. A compound according to claim 18 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein A, L, M, R ¹ , R ³ , X, and m are defined as described in claim 1]
Or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein A, L, M, R ¹ , X and m are defined as described in claim 1]
21. A compound according to claim 20 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M, R ³ and X are defined as described in claim 1]
21. A compound according to claim 20 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M and X are defined as defined in claim 1]
23. A compound according to claim 22 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M, R ³ and X are defined as described in claim 1]
21. A compound according to claim 20 or a pharmaceutically acceptable salt, ester or prodrug thereof. formula:

[Wherein L, M and X are as defined in claim 1]
25. A compound according to claim 24, or a pharmaceutically acceptable salt, ester or prodrug thereof. M is the formula:

A is and each R ⁴ is defined as described in claim 1 is independently a compound according to any one of claims 1 to 25. M is the formula:

A is and R ⁴ is defined as described in claim 1 A compound according to claim 26. M is the formula:

A is and each R ⁴ is defined as described in claim 1 is independently a compound according to any one of claims 1 to 25. M is the formula:

A is and R ⁴ is defined as described in claim 1, claim 28 A compound according.   30. A compound according to any one of claims 1 to 29, wherein X is -NH-. X is the formula:

30. The compound according to any one of claims 1 to 29, wherein   A compound having a structural formula corresponding to any one of the structures exemplified in Table 1, or a pharmaceutically acceptable salt, ester or prodrug thereof.   A pharmaceutical composition comprising one or more of the compounds according to any one of claims 1 to 32 and a pharmaceutically acceptable carrier.   35. A method of treating a microbial infection in a mammal comprising the step of administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating a fungal infection in a mammal comprising the step of administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating a parasitic disease in a mammal comprising administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating a proliferative disease in a mammal comprising administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating a viral infection in a mammal comprising the step of administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating an inflammatory disease in a mammal comprising the step of administering to the mammal one or more effective amount of a compound according to any one of claims 1-32.   35. A method of treating gastrointestinal motility disorders in a mammal comprising the step of administering to the mammal one or more effective amount of a compound according to any one of claims 1-32. 35. A method of treating a disease in a mammal, thereby reducing the symptoms of the disease, comprising administering to the mammal one or more effective amount of a compound according to any one of claims 1-32. Because
The diseases are skin infection, nosocomial pneumonia, pneumonia after viral infection, abdominal infection, urological infection, bacteremia, sepsis, endocarditis, atrioventricular shunt infection, vascular access infection, meningitis The method selected from the group consisting of: postoperative prevention, peritoneal infection, bone infection, joint infection, methicillin-resistant Staphylococcus aureus infection, vancomycin-resistant enterococcal infection, linezolid-resistant biological infection, and tuberculosis.   42. A method according to any one of claims 34 to 41, wherein the compound is administered orally, parenterally or topically.   The manufacturing method of the compound as described in any one of Claims 1-32.   A medical device containing one or more compounds according to any one of claims 1 to 32.   45. The medical device of claim 44, wherein the device is a stent.